Hepatitis B core protein modulators

ABSTRACT

The present disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application under 35 U.S.C. § 120 ofU.S. patent application Ser. No. 15/760,284 filed Mar. 15, 2018, whichis a U.S. National Phase Application under 35 U.S.C. § 371 ofInternational Application PCT/US2016/051934, filed Sep. 15, 2016, whichclaims priority to U.S. Provisional Application No. 62/218,815, filedSep. 15, 2015, each of which is hereby incorporated by reference in itsentirety.

BACKGROUND

Hepatitis B (HBV) causes viral Hepatitis that can further lead tochronic liver disease and increase the risk of liver cirrhosis and livercancer (hepatocellular carcinoma). Worldwide, about 2 billion peoplehave been infected with HBV, around 360 million people are chronicallyinfected, and every year HBV infection causes more than one half milliondeaths (2009; WHO, 2009). HBV can be spread by body fluids: from motherto child, by sex, and via blood products. Children born to HBV-positivemothers may also be infected, unless vaccinated at birth.

The virus particle is composed of a lipid enveloped studded with surfaceprotein (HBsAg) that surrounds the viral core. The core is composed of aprotein shell, or capsid, built of 120 core protein (Cp) dimers, whichin turn contains the relaxed circular DNA (rcDNA) viral genome as wellas viral and host proteins. In an infected cell, the genome is found asa covalently closed circular DNA (cccDNA) in the host cell nucleus. ThecccDNA is the template for viral RNAs and thus viral proteins. In thecytoplasm, Cp assembles around a complex of full-length viral RNA (theso-called pregenomic RNA or pgRNA and viral polymerase (P). Afterassembly, P reverse transcribes the pgRNA to rcDNA within the confinesof the capsid to generate the DNA-filled viral core. For convenience, wedivide the assembly process at the point of capsid assembly andpgRNA-packaging. Steps preceding this event are “upstream”; stepsfollowing RNA-packaging are “downstream”.

At present, chronic HBV is primarily treated with nucleos(t)ide analogs(e.g. entecavir) that suppress the virus while the patient remains ontreatment but do not eliminate the infection, even after many years oftreatment. Once a patient starts taking nucleotide analogs most mustcontinue taking them or risk the possibility of a life threateningimmune response to viral rebound. Further, nucleos(t)ide therapy maylead to the emergence of antiviral drug resistance (Deres andRubsamen-Waigmann, 1999; Tennant et al., 1998; Zhang et al., 2003)and—in rare patients—adverse events have been reported (Ayoub andKeeffe, 2011).

The only FDA approved alternative to nucleos(t)ide analogs is treatmentwith interferon α or pegylated interferon α. Unfortunately, the adverseevent incidence and profile of interferon α can result in poortolerability, and many patients are unable to complete therapy.Moreover, only a small percentage of patients are considered appropriatefor interferon therapy, as only a small subset of patients are likely tohave a sustained clinical response to a course of interferon therapy. Asa result, interferon based therapies are used in only a small percentageof all diagnosed patients who elect for treatment.

Thus, current HBV treatments can range from palliative to watchfulwaiting. Nucleos(t)ide analogs suppress virus production, treating thesymptom, but leave the infection intact. Interferon α has severe sideeffects and less tolerability among patients and is successful as afinite treatment strategy in only a small minority of patients. There isa clear on-going need for more effective treatments for HBV infections.

SUMMARY

Provided herein are compounds that can have properties such as thosedescribed below, where the compounds in some embodiments may berepresented by:

wherein

R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^(c), R^(m), R^(m′), R⁷⁷, R⁷⁸, R^(Z) and Yare defined herein. Also provided herein are methods of treating viralinfections, such as hepatitis B, comprising administering to patient adisclosed compound.

For example, the present disclosure is directed in part to compoundshaving allosteric effector properties against Hepatitis B virus Cp, aprotein found as a dimer, a multimer, and as the protein shell of theHBV core. Without being bound by theory, disclosed compounds mayultimately target multimerization of viral core proteins, which iscentral to HBV infection, where the core protein multimerizes intoshell, or capsid, and/or disclosed compounds may for example, ultimatelytarget interaction of viral core proteins with other macromolecules,such as host or viral nucleic acid, host proteins, or other viralproteins. For example, disclosed compounds may be considered in someembodiments CpAM—core protein allosteric modifiers. CpAM interactionwith core protein can allosterically favor an assembly-active form of Cpdimer and lead to viral capsid assembly at an inappropriate time orplace or lead to non-standard intersubunit interactions, all resultingin defective capsids. CpAMs may additionally or alternatively affectsteps of “upstream” of capsid assembly by altering the concentrations ornature of Cp available as dimer as compared to capsid or othermultimeric forms. Disclosed compounds or CpAMs may, in some embodiments,noticeably affect functions upstream of viral assembly such asmodulation of cccDNA transcription, RNA stability and/or protein-proteininteractions.

DETAILED DESCRIPTION

The features and other details of the disclosure will now be moreparticularly described. Before further description of the presentinvention, certain terms employed in the specification, examples andappended claims are collected here. These definitions should be read inlight of the remainder of the disclosure and as understood by a personof skill in the art. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by a person of ordinary skill in the art.

Definitions

As intended herein, the terms “a” and “an” include singular as well asplural references unless the context clearly dictates otherwise. Forexample, the term “an assembly effector” can include one or more sucheffectors.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon. Exemplary alkyl groups include, but are notlimited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbonatoms, referred to herein as C₁₋₆alkyl, C₁₋₄alkyl, and C₁₋₃alkyl,respectively. Exemplary alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond.Exemplary alkenyl groups include, but are not limited to, a straight orbranched group of 2-6 or 3-4 carbon atoms, referred to herein asC₂₋₆alkenyl, and C₃₋₄alkenyl, respectively. Exemplary alkenyl groupsinclude, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

The term “alkoxy” as used herein refers to a straight or branched alkylgroup attached to oxygen (alkyl-O—). Exemplary alkoxy groups include,but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms,referred to herein as C₁₋₆alkoxy, and C₂₋₆alkoxy, respectively.Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy,isopropoxy, etc.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond.Exemplary alkynyl groups include, but are not limited to, straight orbranched groups of 2-6, or 3-6 carbon atoms, referred to herein asC₂₋₆alkynyl, and C₃₋₆alkynyl, respectively. Exemplary alkynyl groupsinclude, but are not limited to, ethynyl, propynyl, butynyl, pentynyl,hexynyl, methylpropynyl, etc.

The terms “cycloalkyl” or a “carbocyclic group” as used herein refers toa saturated or partially unsaturated hydrocarbon group of, for example,3-6, or 4-6 carbons, referred to herein as C₃₋₆cycloalkyl orC₄₋₆cycloalkyl, respectively. Exemplary cycloalkyl groups include, butare not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutylor cyclopropyl.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The terms “heteroaryl” or “heteroaromatic group” as used herein refersto a monocyclic aromatic 5-6 membered ring system containing one or moreheteroatoms, for example one to three heteroatoms, such as nitrogen,oxygen, and sulfur. Where possible, said heteroaryl ring may be linkedto the adjacent radical though carbon or nitrogen. Examples ofheteroaryl rings include but are not limited to furan, thiophene,pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole,triazole, pyridine or pyrimidine etc.

The terms “heterocyclyl” or “heterocyclic group” are art-recognized andrefer to saturated or partially unsaturated 4-7 membered ringstructures, whose ring structures include one to three heteroatoms, suchas nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings maybe linked to the adjacent radical through carbon or nitrogen. Examplesof heterocyclyl groups include, but are not limited to, pyrrolidine,piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine,tetrahydrofuran or dihydrofuran etc.

The terms “hydroxy” and “hydroxyl” as used herein refers to the radicalOH.

“Treatment” as used herein includes the alleviation, prevention,reversal, amelioration or control of a pathology, disease, disorder,process, condition or event, including viral infection. In this context,the term “treatment” is further to be understood as embracing the use ofa drug to inhibit, block, reverse, restrict or control progression ofviral infection.

As used herein, the term “pharmaceutical composition” refers tocompositions of matter comprising at least one pharmaceutical compoundand optionally a pharmaceutically acceptable carrier.

As used herein, the term “pharmaceutical compound” or “drug” refers to afree compound, its therapeutically suitable salts, solvates such ashydrates, specific crystal forms of the compound or its salts, ortherapeutically suitable prodrugs of the compound.

Pharmaceutically or pharmacologically acceptable” include molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate. For human administration, preparations should meetsterility, pyrogenicity, and general safety and purity standards asrequired by FDA Office of Biologics standards.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” as used herein refers to any and all solvents,dispersion media, coatings, isotonic and absorption delaying agents, andthe like, that are compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. The compositions may also contain other activecompounds providing supplemental, additional, or enhanced therapeuticfunctions.

The compounds of the disclosure may contain one or more chiral centersand, therefore, exist as stereoisomers. The term “stereoisomers” whenused herein consist of all enantiomers or diastereomers. These compoundsmay be designated by the symbols “(+),” “(−),” “R” or “S,” depending onthe configuration of substituents around the stereogenic carbon atom,but the skilled artisan will recognize that a structure may denote achiral center implicitly. The present invention encompasses variousstereoisomers of these compounds and mixtures thereof. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

The compounds of the disclosure may contain one or more double bondsand, therefore, exist as geometric isomers resulting from thearrangement of substituents around a carbon-carbon double bond. Thesymbol denotes a bond that may be a single, double or triple bond asdescribed herein. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “E” configuration wherein the terms“Z” and “E” are used in accordance with IUPAC standards. Unlessotherwise specified, structures depicting double bonds encompass boththe “E” and “Z” isomers. Substituents around a carbon-carbon double bondalternatively can be referred to as “cis” or “trans,” where “cis”represents substituents on the same side of the double bond and “trans”represents substituents on opposite sides of the double bond.

Compounds of the disclosure may contain a carbocyclic or heterocyclicring and therefore, exist as geometric isomers resulting from thearrangement of substituents around the ring. The arrangement ofsubstituents around a carbocyclic or heterocyclic ring are designated asbeing in the “Z” or “E” configuration wherein the terms “Z” and “E” areused in accordance with IUPAC standards. Unless otherwise specified,structures depicting carbocyclic or heterocyclic rings encompass both“Z” and “E” isomers. Substituents around a carbocyclic or heterocyclicrings may also be referred to as “cis” or “trans”, where the term “cis”represents substituents on the same side of the plane of the ring andthe term “trans” represents substituents on opposite sides of the planeof the ring. Mixtures of compounds wherein the substituents are disposedon both the same and opposite sides of plane of the ring are designated“cis/trans.”

Individual enantiomers and diastereomers of compounds of the presentinvention can be prepared synthetically from commercially availablestarting materials that contain asymmetric or stereogenic centers, or bypreparation of racemic mixtures followed by resolution methods wellknown to those of ordinary skill in the art. These methods of resolutionare exemplified by (1) attachment of a mixture of enantiomers to achiral auxiliary, separation of the resulting mixture of diastereomersby recrystallization or chromatography and liberation of the opticallypure product from the auxiliary, (2) salt formation employing anoptically active resolving agent, (3) direct separation of the mixtureof optical enantiomers on chiral liquid chromatographic columns or (4)kinetic resolution using stereoselective chemical or enzymatic reagents.Racemic mixtures can also be resolved into their component enantiomersby well-known methods, such as chiral-phase liquid chromatography orcrystallizing the compound in a chiral solvent. Stereoselectivesyntheses, a chemical or enzymatic reaction in which a single reactantforms an unequal mixture of stereoisomers during the creation of a newstereocenter or during the transformation of a pre-existing one, arewell known in the art. Stereoselective syntheses encompass both enantio-and diastereoselective transformations, and may involve the use ofchiral auxiliaries. For examples, see Carreira and Kvaerno, Classics inStereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

The compounds disclosed herein can exist in solvated as well asunsolvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. In one embodiment, thecompound is amorphous. In one embodiment, the compound is a singlepolymorph. In another embodiment, the compound is a mixture ofpolymorphs. In another embodiment, the compound is in a crystallineform.

The invention also embraces isotopically labeled compounds of theinvention which are identical to those recited herein, except that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. For example,a compound of the invention may have one or more H atom replaced withdeuterium.

Certain isotopically-labeled disclosed compounds (e.g., those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in the examples herein by substituting an isotopically labeledreagent for a non-isotopically labeled reagent.

The term “therapeutically suitable salt,” refers to salts or zwitterionsof pharmaceutical compounds which are water or oil-soluble ordispersible, suitable for treatment of disorders and effective for theirintended use. The salts may be prepared, for instance, during the finalisolation and purification of the compounds or separately by reacting anamino group of the compounds with a suitable acid. For example, acompound may be dissolved in a suitable solvent, such as but not limitedto methanol and water, and treated with at least one equivalent of anacid, for instance hydrochloric acid. The resulting salt may precipitateout and be isolated by filtration and dried under reduced pressure.Alternatively, the solvent and excess acid may be removed under reducedpressure to provide the salt. Representative salts include acetate,adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,glycerophosphate, hemisulfate, heptanoate, hexanoate, formate,isethionate, fumarate, lactate, maleate, methanesulfonate,naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate,propionate, succinate, tartrate, trichloroacetate, trifluoroacetate,glutamate, para-toluenesulfonate, undecanoate, hydrochloric,hydrobromic, sulfuric, phosphoric, and the like. The amino groups of acompound may also be quaternized with alkyl chlorides, bromides, andiodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl,myristyl, stearyl, and the like.

Basic addition salts may be prepared, for instance, during the finalisolation and purification of pharmaceutical compounds by reaction of acarboxyl group with a suitable base such as the hydroxide, carbonate, orbicarbonate of a metal cation such as lithium, sodium, potassium,calcium, magnesium, or aluminum, or an organic primary, secondary, ortertiary amine. Quaternary amine salts may be derived, for example, frommethylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,ethylamine, tributylamine, pyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine,dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, andN,N′-dibenzylethylenediamine, ethylenediamine, ethanolamine,diethanolamine, piperidine, piperazine, and the like.

The term “therapeutically suitable prodrug,” refers to those prodrugs orzwitterions which are suitable for use in contact with the tissues ofsubjects and are effective for their intended use. The term “prodrug”refers to compounds that are transformed in vivo to a pharmaceuticalcompound, for example, by hydrolysis in blood. The term “prodrug,”refers to compounds that contain, but are not limited to, substituentsknown as “therapeutically suitable esters.” The term “therapeuticallysuitable ester,” refers to alkoxycarbonyl groups appended to the parentmolecule on an available carbon atom. More specifically, a“therapeutically suitable ester,” refers to alkoxycarbonyl groupsappended to the parent molecule on one or more available aryl,cycloalkyl and/or heterocycle groups. Compounds containingtherapeutically suitable esters are an example, but are not intended tolimit the scope of compounds considered to be prodrugs. Examples ofprodrug ester groups include pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, as well as other such groupsknown in the art. Other examples of prodrug ester groups are found in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Series, and in Edward B. Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein byreference.

The terms “pharmaceutically effective amount” and “effective amount”, asused herein, refer to an amount of a pharmaceutical formulation thatwill elicit the desired therapeutic effect or response when administeredin accordance with the desired treatment regimen. US2011/0144086describes the use of some diabenzothiazepine molecules (DBTs) asanti-malarial “inhibitors of the plasmodial surface anion channel.”However, no study of DBT molecules as anti-virals has yet been reported.

In an embodiment, provided herein are compounds represented by:

wherein

-   -   Y is selected from the group consisting of S(O)_(y), C═O,        C(R¹¹)₂, NR_(Y) and O wherein y is 0, 1, or 2;

R¹¹, for each occurrence, is selected from the group consisting of H,halogen, and C₁₋₆alkyl (optionally substituted with one, two, or threehalogens);

R_(Y) is selected from the group consisting of H, methyl, ethyl, propyl,propenyl, butyl, phenyl and benzyl, wherein R_(Y) when not H may beoptionally substituted by hydroxyl;

R^(Z) is selected from the group consisting of H, methyl, ethyl, propyl,phenyl and benzyl;

R^(m′) and R^(m) are each independently selected from the groupconsisting of H, C₁₋₆alkyl (optionally substituted by one, two or threesubstituents each independently selected from halogen and hydroxyl), andC₂₋₆alkenyl (optionally substituted by one, two or three substituentseach independently selected from halogen and hydroxyl);

R^(c) is selected from the group consisting of H, C₁₋₆alkyl andC₂₋₆alkenyl;

R⁷⁷ is selected from the group consisting of H, halogen, cyano, andC₁₋₆alkyl;

R⁷⁸ is selected from the group consisting of H, halogen, cyano,C₁₋₆alkyl, carboxy, —C(O)—O—C₁₋₆alkyl; C₃₋₆cycloalkyl, —NR′R″; phenyl(optionally substituted with one, two, three or four substituents eachindependently selected from the group consisting of R⁷³); benzyl(optionally substituted with one or more substituents each independentlyselected from the group consisting of R⁷³), 4-7 membered heterocycle(optionally substituted with one or more substituents each independentlyselected from the group consisting of R⁷³); 4-6 membered monocyclicheteroaryl (optionally substituted with one or more substituents eachindependently selected from the group consisting of R⁷³); 9-10 memberedbicyclic heteroaryl (optionally substituted with one or moresubstituents each independently selected from the group consisting ofR⁷³), X²—R⁷⁹, and X²—C₁₋₆alkylene-R⁷⁹;

X² is selected from the group consisting of S(O)_(w) (wherein w is 0, 1,or 2), O, —C(O)— and NR′;

R⁷⁹ is selected from the group consisting of H, hydroxyl, halogen,C₁₋₆alkyl, —C(O)—O—C₁₋₆alkyl, heterocycle (optionally substituted by oneor more substituents selected from the group consisting of halogen,NR′R′, —C(O)—O—C₁₋₆alkyl, carboxy and C₁₋₆alkyl), —C(O)—NR′R″,—C(═NH)—NR′R″, heteroaryl, phenyl (optionally substituted by one or moresubstituents selected from the group consisting of halogen, NR′R′,—C(O)—O—C₁₋₆alkyl, carboxy, C₁₋₆alkoxy, and C₁₋₆alkyl), C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, carboxy, NR′R″, —C(O)—C₁₋₆alkyl,C₃₋₆cycloalkyl, —NR′—C(O)—C₁₋₆alkyl, NR′—C(O)—O—C₁₋₆alkyl,—S(O)_(w)—C₁₋₆alkyl (where w is 0, 1 or 2), —S(O)_(w)—NR′R″ (where w is0, 1 or 2), and —NR′—S(O)_(w)—C₁₋₆alkyl (where w is 0, 1 or 2));

R⁷³ is selected from the group consisting of H, halogen, hydroxyl,nitro, cyano, carboxy, oxo, C₁₋₆alkyl, —C(O)—O—C₁₋₆alkyl, heterocycle(optionally substituted by one or more substituents selected from thegroup consisting of halogen, hydroxyl, oxo, NR′R′, —C(O)—O—C₁₋₆alkyl,carboxy and C₁₋₆alkyl), —C(O)—NR′—C₁₋₆alkyl, —C(═NH)—NR′R″, heteroaryl,phenyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, carboxy, oxo, NR′R″,—C(O)—C₁₋₆alkyl, —C₃₋₆cycloalkyl, NR′—C(O)—C₁₋₆alkyl,NR′—C(O)—O—C₁₋₆alkyl, —S(O)_(w)—C₁₋₆alkyl (where w is 0, 1 or 2),—S(O)_(w)—NR′R″ (where w is 1, 2 or 3), —NR′—S(O)_(w)—C₁₋₆alkyl (where wis 0, 1 or 2), C(O)—NR′—C₁₋₆alkyl,C(O)—C₁₋₃alkylene-NR′—C(O)—O—C₁₋₆alkyl, X²—R⁷⁹; and X²—C₁₋₆alkylene-R⁷⁹;

R′ is selected, independently for each occurrence, from H, methyl,ethyl, cyclopropyl, cyclobutyl, and propyl;

R″ is selected, independently for each occurrence, from H, methyl,ethyl, propyl, (optionally substituted by hydroxyl), butyl (optionallysubstituted by hydroxyl), —C(O)-methyl and —C(O)-ethyl, or R′ and R″taken together with the nitrogen to which they are attached may form a4-7 membered heterocycle optionally substituted by one, two or moresubstituents selected from the group consisting of halogen, hydroxyl,NH₂, —C(O)—O—C₁₋₃alkyl, —C(O)—C₁₋₃alkyl, carboxy, oxo, and C₁₋₃alkyl;

each of moieties R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independentlyselected for each occurrence from the group consisting of hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy, C₂₋₆alkynyl, C₂₋₆ alkenyl, halogen, hydroxyl,nitro, cyano, and NR′R″;

wherein for each occurrence, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl maybe optionally substituted with one, two, three or more substituentsselected from the group consisting of halogen, hydroxyl, nitro, cyano,carboxy, C₃₋₆cycloalkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₃alkoxy, NR′R″,—NR′—S(O)_(w)—C₁₋₂alkyl (where w is 0, 1 or 2), NR′—C(O)—C₁₋₃alkyl,NR′—C(O)—O—C₁₋₃alkyl, and S(O)_(w)—NR′R″(where w is 0, 1 or 2);C₁₋₆alkoxy may be optionally substituted with one, two, three or moresubstituents selected from the group consisting of halogen, hydroxyl,nitro, cyano, carboxy, NR′R″, —NR′—S(O)_(w)—C₁₋₂alkyl (where w is 0, 1or 2), and S(O)_(w)—NR′R″ (where w is 0, 1 or 2); C₁₋₆alkylene may beoptionally substituted by a substituent selected from the groupconsisting of C₃₋₆cycloalkyl, hydroxyl, cyano, and halogen;

and pharmaceutically acceptable salts and N-oxides thereof.

In some embodiments, Y may be selected from the group consisting ofS(O)_(y), C═O, C(R¹¹)₂, and O For example, Y may be S(O)_(y).

In an embodiment, y may be 1 or 2. In another embodiment, y may be 0. Ina further embodiment, y may be 1. In another other embodiment, y may be2.

For example, in some embodiments Y may be C═O. In some embodiments, Ymay be NH.

For example, in some embodiments R⁷⁸ may be selected from the groupconsisting of C₁₋₆ alkyl substituted with one, two, or threesubstituents each independently selected from the group consisting ofhalogen, hydroxyl, and cyano; phenyl substituted with one, two, three orfour substituents each independently selected from the group consistingof R⁷³; and X²—C₁₋₆alkylene-R⁷⁹.

For example, in some embodiments R⁷⁸ may be selected from the groupconsisting of CF₃, cyano, and phenyl substituted with one, two, three orfour substituents each independently selected from the group consistingof R⁷³.

For example, in some embodiments R⁷⁸ may be selected from the groupconsisting of phenyl substituted with one, two, three or foursubstituents each independently selected from the group consisting ofR⁷³; benzyl (optionally substituted with one or more substituents eachindependently selected from the group consisting of R⁷³), pyridinyl(optionally substituted with one or more substituents each independentlyselected from the group consisting of R⁷³), pyrimidinyl (optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of R⁷³), benzoimidazole (optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of R⁷³), quinolinyl (optionally substitutedwith one or more substituents each independently selected from the groupconsisting of R⁷³, thiazolyl, and pyrazolyl (optionally substituted withone or more substituents each independently selected from the groupconsisting of R⁷³).

For example, in some embodiments R⁷⁸ may be —NR′R″, wherein R′ and R″taken together with the nitrogen to which they are attached may form a4-7 membered heterocycle optionally substituted by one, two or moresubstituents selected from the group consisting of halogen, hydroxyl,NH₂, —C(O)—O—C₁₋₃alkyl, —C(O)—C₁₋₃alkyl, carboxy, oxo, and C₁₋₃alkyl.

In one embodiment, R⁷⁷ may be H. In some embodiments, R⁷ may be H orhalogen.

In another embodiment, R¹⁹ may be H, halogen or methyl.

In certain embodiments, R^(m′) and R^(m) may be each H. In otherembodiments, R^(Z) may be H.

For example, in some embodiments each of R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰may be H.

Also provided herein are compounds represented by:

wherein

R⁷³ is selected from the group consisting of heterocycle (optionallysubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxyl, oxo, NR′R′, —C(O)—O—C₁₋₆alkyl, carboxyand C₁₋₆alkyl), —C(O)—NR′—C₁₋₆alkyl, —C(═NH)—NR′R″, heteroaryl(optionally substituted by one or more substituents selected from thegroup consisting of halogen, hydroxyl, NR′R′, —C(O)—O—C₁₋₆alkyl, carboxyand C₁₋₆alkyl), phenyl (optionally substituted by one or moresubstituents selected from the group consisting of halogen, hydroxyl,oxo, NR′R′, —C(O)—O—C₁₋₆alkyl, carboxy and C₁₋₆alkyl), C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, carboxy, —C(O)—C₁₋₆alkyl, —C₃₋₆cycloalkyl,NR′—C(O)—C₁₋₆alkyl, NR′—C(O)—O—C₁₋₆alkyl, —S(O)_(w)—C₁₋₆alkyl (where wis 0, 1 or 2), —S(O)_(w)—NR′R″ (where w is 0, 1 or 2),—NR′—S(O)_(w)—C₁₋₆alkyl (where w is 0, 1 or 2), C(O)—NR′—C₁₋₆alkyl,C(O)—C₁₋₃alkylene-NR′—C(O)—O—C₁₋₆alkyl, X²—R⁷⁹; and X²—C₁₋₆alkylene-R⁷⁹;

R⁶⁸ is independently selected for each occurrence from the groupconsisting of H, halogen, hydroxyl, C₁₋₆alkyl and C₁₋₆alkoxy;

X² is selected from the group consisting of S(O)_(w) (wherein w is 0, 1,or 2), O, —C(O)— and NR′;

R⁷⁹ is selected from the group consisting of H, hydroxyl, halogen,C₁₋₆alkyl, —C(O)—O—C₁₋₆alkyl, heterocycle (optionally substituted by oneor more substituents selected from the group consisting of halogen,NR′R′, —C(O)—O—C₁₋₆alkyl, carboxy and C₁₋₆alkyl), —C(O)—NR′R″,—C(═NH)—NR′R″, heteroaryl, phenyl (optionally substituted by one or moresubstituents selected from the group consisting of halogen, NR′R′,—C(O)—O—C₁₋₆alkyl, carboxy, C₁₋₆alkoxy, and C₁₋₆alkyl), C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, carboxy, NR′R″, —C(O)—C₁₋₆alkyl,C₃₋₆cycloalkyl, —NR′—C(O)—C₁₋₆alkyl, NR′—C(O)—O—C₁₋₆alkyl,—S(O)_(w)—C₁₋₆alkyl (where w is 0, 1 or 2), —S(O)_(w)—NR′R″ (where w is0, 1 or 2), and —NR′—S(O)_(w)—C₁₋₆alkyl (where w is 0, 1 or 2));

R′ is selected, independently for each occurrence, from H, methyl,ethyl, cyclopropyl, cyclobutyl, and propyl;

R″ is selected, independently for each occurrence, from H, methyl,ethyl, propyl, (optionally substituted by hydroxyl), butyl (optionallysubstituted by hydroxyl), —C(O)-methyl and —C(O)-ethyl, or R′ and R″taken together with the nitrogen to which they are attached may form a4-7 membered heterocycle optionally substituted by one, two or moresubstituents selected from the group consisting of halogen, hydroxyl,NH₂, —C(O)—O—C₁₋₃alkyl, —C(O)—C₁₋₃alkyl, carboxy, oxo, and C₁₋₃alkyl;

each of moieties R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independentlyselected for each occurrence from the group consisting of hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy, C₂₋₆alkynyl, C₂₋₆ alkenyl, halogen, hydroxyl,nitro, cyano, and NR′R″;

wherein for each occurrence, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl maybe optionally substituted with one, two, three or more substituentsselected from the group consisting of halogen, hydroxyl, nitro, cyano,carboxy, C₃₋₆cycloalkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₃alkoxy, NR′R″,—NR′—S(O)_(w)—C₁₋₂alkyl (where w is 0, 1 or 2), NR′—C(O)—C₁₋₃alkyl,NR′—C(O)—O—C₁₋₃alkyl, and S(O)_(w)—NR′R″(where w is 0, 1 or 2);C₁₋₆alkoxy may be optionally substituted with one, two, three or moresubstituents selected from the group consisting of halogen, hydroxyl,nitro, cyano, carboxy, C₁₋₃alkyl, NR′R″, —NR′—S(O)_(w)—C₁₋₂alkyl (wherew is 0, 1 or 2), and S(O)_(w)—NR′R″ (where w is 0, 1 or 2); C₁₋₆alkylenemay be optionally substituted by a substituent selected from the groupconsisting of C₃₋₆cycloalkyl, hydroxyl, cyano, and halogen;

and pharmaceutically acceptable salts and N-oxides thereof.

Also provided herein are compounds represented by:

wherein

-   -   Y is selected from the group consisting of S(O)_(y), C═O,        C(R¹¹)₂, NR_(Y) and O wherein y is 0, 1, or 2;

R_(Y) is selected from the group consisting of H, methyl, ethyl, propyl,propenyl, butyl, phenyl and benzyl;

R^(Z) is selected from the group consisting of H, methyl, ethyl, propyl,phenyl and benzyl;

R^(c) is selected from the group consisting of H, C₁₋₆alkyl andC₂₋₆alkenyl;

X² is selected from the group consisting of S(O)_(w) (wherein w is 0, 1,or 2), O, —C(O)— and NR′;

R⁵⁸ and R⁵⁹ are each independently selected from the group consisting ofH, halogen, hydroxyl, nitro, cyano, carboxy, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, NR′R″, —C(O)—C₁₋₆alkyl, —C(O)—C₁₋₆alkoxy,phenyl, heteroaryl, C₃₋₆cycloalkyl, —S(O)_(w)—C₁₋₆alkyl (where w is 0, 1or 2), —S(O)_(w)—NR′R″ (where w is 0, 1 or 2), and—NR′—S(O)_(w)—C₁₋₆alkyl (where w is 0, 1 or 2); or form a phenyl,heterocyclic or heteroaryl ring (optionally substituted by one, two, orthree substituents selected from the group consisting of hydrogen,C₁₋₆alkyl, C₂₋₆alkynyl, C₂₋₆ alkenyl, halogen, hydroxyl, nitro, cyano,and NR′R″) and fused to the ring to which they are attached;

R′ is selected, independently for each occurrence, from H, methyl,ethyl, cyclopropyl, cyclobutyl, and propyl;

R″ is selected, independently for each occurrence, from H, methyl,ethyl, propyl (optionally substituted by hydroxyl), butyl (optionallysubstituted by hydroxyl), C(O)-methyl and C(O)-ethyl, or R′ and R″ takentogether with the nitrogen to which they are attached may form a 4-6membered heterocycle optionally substituted by one or more substituentsselected from the group consisting of halogen, NH₂, —C(O)—O—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, carboxy and C₁₋₆alkyl;

R¹¹, for each occurrence, is selected from the group consisting of H,halogen, and C₁₋₆alkyl (optionally substituted with one, two, or threehalogens);

each of moieties R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independentlyselected for each occurrence from the group consisting of hydrogen,C₁₋₆alkyl, C₂₋₆alkynyl, C₂₋₆alkenyl, halogen, hydroxyl, nitro, cyano,and NR′R″;

wherein for each occurrence, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl maybe optionally substituted with one, two, three or more substituentsselected from the group consisting of halogen, hydroxyl, nitro, cyano,carboxy, C₃₋₆cycloalkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₃alkoxy, NR′R″,—NR′—S(O)_(w)—C₁₋₂alkyl (where w is 0, 1 or 2), NR′—C(O)—C₁₋₃alkyl,NR′—C(O)—O—C₁₋₃alkyl, —NR′—S(O)_(w), and S(O)_(w)—NR′R″; C₁₋₆alkoxy maybe optionally substituted with one, two, three or more substituentsselected from the group consisting of halogen, hydroxyl, nitro, cyano,carboxy, C₁₋₃alkyl, NR′R″, C₁₋₂alkyl (where w is 0, 1 or 2), andS(O)_(w)—NR′R″ (where w is 0, 1 or 2); C₁₋₆alkylene may be optionallysubstituted by a substituent selected from the group consisting ofC₃₋₆cycloalkyl, hydroxyl, cyano, and halogen;

and pharmaceutically acceptable salts and N-oxides thereof.

For example, in some embodiments, Y may be selected from the groupconsisting of S(O)_(y), C═O, C(R¹¹)₂, NR_(Y) and O wherein y is 0, 1, or2.

For example, the present disclosure also provides, in part, a compoundselected from the group consisting a compound described in the Examplesbelow and pharmaceutically acceptable salts thereof. In an embodiment,the present disclosure provides a pharmaceutically acceptablecomposition comprising a disclosed compound, and a pharmaceuticallyacceptable excipient.

For example, the present disclosure also provides, in part, a compoundselected from the group consisting of(S)-11-oxo-N-((2-(4-(2-(pyrrolidin-2-yl)ethoxy)phenyl)thiazol-5-yl)methyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;(S)—N-((2-(4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide; (R)—N-((2-(4-((1methylpyrrolidin-3-yl)methoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;(E)-N-((2-(4-(3-hydroxyprop-1-en-1-yl)-1H-pyrazol-1-yl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(3-(dimethylamino)propyl)-1H-pyrazol-1-yl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(3-hydroxypropyl)-1H-pyrazol-1-yl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;11-oxo-N-((2-(4-(4-(piperidin-1-yl)but-1-yn-1-yl)phenyl)thiazol-5-yl)methyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(4-(diethylamino)but-1-yn-1-yl)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;11-oxo-N-((2-(5-(3-(piperidin-1-yl)propoxy)pyridin-2-yl)thiazol-5-yl)methyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(5-(3-morpholinopropoxy)pyridin-2-yl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(5-(3-(diethylamino)propoxy)pyridin-2-yl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;11-oxo-N-((2-(5-(4-(piperidin-1-yl)butyl)pyridin-2-yl)thiazol-5-yl)methyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(5-(4-morpholinobutyl)pyridin-2-yl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(5-(4-(diethylamino)butyl)pyridin-2-yl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;(R)-4-(3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)morpholine-3-carboxylicacid;(S)-4-(3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)morpholine-3-carboxylicacid;(S)—N-((2-(4-(3-(3-methylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;(R)—N-((2-(4-(3-(3-methylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;(R)—N-((2-(4-(3-(2-methylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;(S)—N-((2-(4-(3-(2-methylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(3-(dimethylamino)propoxy)cyclohexyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(3-((2R,6R)-2,6-dimethylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(3-((2S,6S)-2,6-dimethylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(3-((2R,6S)-2,6-dimethylmorpholino)propoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(5-(3-hydroxypropoxy)pyridin-2-yl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(3-(cyclobutyl(methyl)amino)propoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;11-oxo-N-((2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)thiazol-5-yl)methyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide; methyl(3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-D-prolinate;(3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-D-proline;ethyl(3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-L-prolinate;isopropyl(3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-L-prolinate;methyl(S)-4-(3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)morpholine-3-carboxylate;methyl(3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-L-alaninate;(3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-L-alanine;methylN-(3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-N-methyl-L-alaninate;N-(3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-N-methyl-L-alanine;methyl(3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-L-valinate;(3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-L-valine;methyl(2-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)ethyl)-L-prolinate;(2-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)ethyl)-L-proline;methyl(4-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenyl)but-3-yn-1-yl)-L-prolinate;(4-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenyl)but-3-yn-1-yl)-L-proline;N-((2-(4-cyano-1H-pyrazol-1-yl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-((1-ethylpiperidin-4-yl)oxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(3-morpholinopropyl)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide; methyl(3-(4-(5-((9-methyl-5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-L-prolinate;(3-(4-(5-((9-methyl-5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)propyl)-L-proline;N-((2-(4-cyano-1H-pyrazol-1-yl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;9-methyl-N-((2-(4-(2-morpholinoethoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;9-methyl-11-oxo-N-((2-(4-(piperidin-4-yloxy)phenyl)thiazol-5-yl)methyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-((1-ethylpiperidin-4-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-1-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;(S)—N-((2-(4-(3-(2-(hydroxymethyl)pyrrolidin-1-yl)propoxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;(S)—N-((2-(4-(3-(2-(methoxymethyl)pyrrolidin-1-yl)propoxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;(S)—N-((2-(4-(3-(2-cyanopyrrolidin-11-yl)propoxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;(S)—N-((2-(4-(3-(2-(1H-tetrazol-5-yl)pyrrolidin-1-yl)propoxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;9-methyl-N-((2-(4-(4-morpholinobut-1-yn-1-yl)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;9-methyl-N-((2-(4-(4-morpholinobutyl)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4,4-difluoropiperidin-1-yl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-methoxypiperidin-1-yl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;9-methyl-N-((2-(4-(3-morpholinopropyl)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-((1-isopropylpiperidin-4-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-((1-ethylazetidin-3-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-((1-isopropylazetidin-3-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-((3-(dimethylamino)azetidin-1-yl)methyl)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-((3-(diethylamino)azetidin-1-yl)methyl)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-([1,3′-biazetidin]-1′-ylmethyl)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(azetidin-1-ylmethyl)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide; methyl(4-(5-((9-methyl-5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)-L-prolinate;(4-(5-((9-methyl-5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)-L-proline;methyl (S)-4,4-difluoro-1-(4-(5-((9-methyl-5,5-dioxido-11l-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)pyrrolidine-2-carboxylate;(S)-4,4-difluoro-1-(4-(5-((9-methyl-5,5-dioxido-1-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)pyrrolidine-2-carboxylicacid; methyl (S)-4-(4-(5-((9-methyl-5,5-dioxido-1l-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)morpholine-3-carboxylate;(S)-4-(4-(5-((9-methyl-5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)morpholine-3-carboxylicacid;N-([2,2′-bithiazol]-5-ylmethyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-([2,4′-bithiazol]-5-ylmethyl)-9-methyl-1-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(3-morpholinopropyl)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;9-methyl-11-oxo-N-((2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-5-yl)methyl)-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;9-methyl-N-((2-(4-(3-morpholinopropoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;N-((2-(4-(3-(diethylamino)propoxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;9-methyl-N-((2-(4-(3-morpholinopropyl)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;9-methyl-N-((2-(4-(2-morpholinoethoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;N-((2-(4-((1-ethylpiperidin-4-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;N-((2-(4-((1-isopropylpiperidin-4-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-1-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;N-((2-(4-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;N-((2-(4-((1-ethylazetidin-3-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;N-((2-(4-((1-isopropylazetidin-3-yl)oxy)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;N-((2-(4-((3-(dimethylamino)azetidin-1-yl)methyl)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;methyl(4-(5-((9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)-L-prolinate;(4-(5-((9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)-L-proline;methyl(S)-4,4-difluoro-1-(4-(5-((9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)pyrrolidine-2-carboxylate;(S)-4,4-difluoro-1-(4-(5-((9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)pyrrolidine-2-carboxylicacid;N-([2,2′-bithiazol]-5-ylmethyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;N-((2-(5-fluoropyridin-2-yl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;N-((2-(5-cyanopyridin-2-yl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;11-oxo-N-((2-(4-(3-(piperidin-1-yl)propyl)-1H-pyrazol-1-yl)thiazol-5-yl)methyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;9-methyl-11-oxo-N-((2-(4-(3-(piperidin-1-yl)propyl)-1H-pyrazol-1-yl)thiazol-5-yl)methyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(3-(azetidin-1-yl)propyl)-1H-pyrazol-1-yl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(4-(azetidin-1-yl)but-1-yn-1-yl)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(4-(azetidin-1-yl)butyl)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;9-methyl-N-((2-(4-(3-morpholinopropyl)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;(S)—N-((2-(4-(3-(2-cyanopyrrolidin-1-yl)propyl)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;N-((2-(4-(3-(azetidin-1-yl)propyl)phenyl)thiazol-5-yl)methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;9-methyl-11-oxo-N-((2-(4-(3-(piperidin-1-yl)propyl)phenyl)thiazol-5-yl)methyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide5,5-dioxide;2-(5-((9-methyl-5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)pyridine1-oxide;9-chloro-N-((2-(5-cyanopyridin-2-yl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide;6-(5-((9-methyl-5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)picolinicacid; methyl(S)-4,4-difluoro-1-(4-(5-((9-methyl-5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)pyrrolidine-2-carboxylate;2-methyl-2-(5-((9-methyl-5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)propanoicacid;(S)-4,4-difluoro-1-(4-(5-((9-methyl-5,5-dioxido-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamido)methyl)thiazol-2-yl)benzyl)pyrrolidine-2-carboxylicacid; and pharmaceutically acceptable salts thereof. In an embodiment,the present disclosure provides a pharmaceutically acceptablecomposition comprising a disclosed compound, and a pharmaceuticallyacceptable excipient.

In a further aspect, a method for treating a hepatitis B infection in apatient in need thereof is provided, comprising administering to asubject or patient an effective amount of a disclosed compound, and/oradministering a first disclosed compound and optionally, and additional,different disclosed compound(s). In another embodiment, a method fortreating a hepatitis B infection in a patient in need thereof isprovided, comprising administering to a subject or patient atherapeutically effective amount of a pharmaceutical compositioncomprising a disclosed compound, or two or more disclosed compounds.

For use in accordance with this aspect, the appropriate dosage isexpected to vary depending on, for example, the particular compoundemployed, the mode of administration, and the nature and severity of theinfection to be treated as well as the specific infection to be treatedand is within the purview of the treating physician. Usually, anindicated administration dose may be in the range between about 0.1 toabout 1000 μg/kg body weight. In some cases, the administration dose ofthe compound may be less than 400 μg/kg body weight. In other cases, theadministration dose may be less than 200 μg/kg body weight. In yet othercases, the administration dose may be in the range between about 0.1 toabout 100 μg/kg body weight. The dose may be conveniently administeredonce daily, or in divided doses up to, for example, four times a day orin sustained release form.

A compound may be administered by any conventional route, in particular:enterally, topically, orally, nasally, e.g. in the form of tablets orcapsules, via suppositories, or parenterally, e.g. in the form ofinjectable solutions or suspensions, for intravenous, intra-muscular,sub-cutaneous, or intra-peritoneal injection. Suitable formulations andpharmaceutical compositions will include those formulated in aconventional manner using one or more physiologically acceptablecarriers or excipients, and any of those known and commerciallyavailable and currently employed in the clinical setting. Thus, thecompounds may be formulated for oral, buccal, topical, parenteral,rectal or transdermal administration or in a form suitable foradministration by inhalation or insufflation (either orally or nasally).

For oral administration, pharmaceutical compositions may take the formof, for example, tablets or capsules prepared by conventional means withpharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Tabletsmay be coated by methods well known in the art. Liquid preparations fororal administration may take the form of, for example, solutions, syrupsor suspensions, or they may be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). Preparations may also contain buffer salts, flavoring, coloringand sweetening agents as appropriate.

Preparations for oral administration may also be suitably formulated togive controlled-release or sustained release of the active compound(s)over an extended period. For buccal administration the compositions maytake the form of tablets or lozenges formulated in a conventional mannerknown to the skilled artisan.

A disclosed compound may also be formulated for parenteraladministration by injection e.g. by bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform e.g. in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containadditives such as suspending, stabilizing and/or dispersing agents.Alternatively, the compound may be in powder form for constitution witha suitable vehicle, e.g. sterile pyrogen-free water, before use.Compounds may also be formulated for rectal administration assuppositories or retention enemas, e.g. containing conventionalsuppository bases such as cocoa butter or other glycerides.

In some cases, a disclosed compound may be administered as part of acombination therapy in conjunction with one or more antivirals. Exampleantivirals include nucleoside analogs, interferon α, and other assemblyeffectors, for instance heteroaryldihydropyrimidines (HAPs) such asmethyl4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate(HAP-1). For example, provided herein is a method of treating patientsuffering from hepatitis B comprising administering to a subject a firstamount of a disclosed compound and a second amount of an antiviral, orother anti HBV agent, for example a second amount of a second compoundselected from the group consisting of: another HBV caspid assemblypromoter (such as certain compounds disclosed herein or for example,GLS4, BAY 41-4109, AT-130, DVR-23 (e.g., as depicted below),

NVR 3-778, NVR1221 (by code); and N890 (as depicted below):

other CpAMs such as those disclosed in the following patent applicationshereby incorporated by reference: WO2014037480, WO2014184328,WO2013006394, WO2014089296, WO2014106019, WO2013102655, WO2014184350,WO2014184365, WO2014161888, WO2014131847, WO2014033176, WO2014033167,and WO2014033170; Nucleoside analogs interfering with viral polymerase,such as entecavir (Baraclude), Lamivudine, (Epivir-HBV), Telbivudine(Tyzeka, Sebivo), Adefovir dipivoxil (Hepsera), Tenofovir (Viread),Tenofovir alafenamide fumarate (TAF), prodrugs of tenofavir (e.g.AGX-1009), L-FMAU (Clevudine), LB80380 (Besifovir) and:

viral entry inhibitors such as Myrcludex B and related lipopeptidederivatives; HBsAg secretion inhibitors such as REP 9AC′ and relatednucleic acid-based amphipathic polymers, HBF-0529 (PBHBV-001),PBHBV-2-15 as depicted below:

and BM601 as depicted below:

disruptors of nucleocapsid formation or integrity such as NZ-4/W28F:

cccDNA formation inhibitors: such as BSBI-25, CCC-0346, CCC-0975 (asdepicted below):

HBc directed transbodies such as those described in Wang Y, et al,Transbody against hepatitis B virus core protein inhibits hepatitis Bvirus replication in vitro, Int. Immunopharmacol (2014), located at//dx.doi.org/10.1016/j.intimp.2015.01.028; antiviral core protein mutant(such as Cp183-V124W and related mutations as described inWO/2013/010069, WO2014/074906 each incorporated by reference);inhibitors of HBx-interactions such as RNAi, antisense and nucleic acidbased polymers targeting HBV RNA; e.g., RNAi (for example ALN-HBV,ARC-520, TKM-HBV, ddRNAi), antisense (ISIS-HBV), or nucleic acid basedpolymer: (REP 2139-Ca); immunostimulants such as Interferon alpha 2a(Roferon), Intron A (interferon alpha 2b), Pegasys (peginterferon alpha2a), Pegylated IFN 2b, IFN lambda 1a and PEG IFN lambda 1a, Wellferon,Roferon, Infergen, lymphotoxin beta agonists such as CBE11 and BS1);Non-Interferon Immune enhancers such as Thymosin alpha-1 (Zadaxin) andInterleukin-7 (CYT107); TLR-7/9 agonists such as GS-9620, CYT003,Resiquimod; Cyclophilin Inhibitors such as NVP018; OCB-030; SCY-635;Alisporivir; NIM811 and related cyclosporine analogs; vaccines such asGS-4774, TG1050, Core antigen vaccine; SMAC mimetics such as birinapantand other IAP-antagonists; Epigenetic modulators such as KMT inhibitors(EZH1/2, G9a, SETD7, Suv39 inhibitors), PRMT inhibitors, HDACinhibitors, SIRT agonists, HAT inhibitors, WD antagonists (e.g.OICR-9429), PARP inhibitors, APE inhibitors, DNMT inhibitors, LSD1inhibitors, JMJD HDM inhibitors, and Bromodomain antagonists; kinaseinhibitors such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors,CDK2 inhibitors, ATM & ATR kinase inhibitors; STING Agonists; Ribavirin;N-acetyl cysteine; NOV-205 (BAM205); Nitazoxanide (Alinia), Tizoxanide;SB 9200 Small Molecule Nucleic Acid Hybrid (SMNH); DV-601; Arbidol; FXRagonists (such as GW 4064 and Fexaramin); antibodies, therapeuticproteins, gene therapy, and biologics directed against viral componentsor interacting host proteins.

In some embodiments, the disclosure provides a method of treating ahepatitis B infection in a patient in need thereof, comprisingadministering a first compound selected from any one of the disclosedcompounds, and one or more other HBV agents each selected from the groupconsisting of HBV capsid assembly promoters, HBF viral polymeraseinterfering nucleosides, viral entry inhibitors, HBsAg secretioninhibitors, disruptors of nucleocapsid formation, cccDNA formationinhibitors, antiviral core protein mutant, HBc directed transbodies,RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilininhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinaseinhibitors, and STING agonists. In some embodiments, the disclosureprovides a method of treating a hepatitis B infection in a patient inneed thereof, comprising administering an amount of a disclosedcompound, and administering another HBV capsid assembly promoter.

In some embodiments, the first and second amounts together comprise apharmaceutically effective amount. The first amount, the second amount,or both may be the same, more, or less than effective amounts of eachcompound administered as monotherapies. Therapeutically effectiveamounts of a disclosed compound and antiviral may be co-administered tothe subject, i.e., administered to the subject simultaneously orseparately, in any given order and by the same or different routes ofadministration. In some instances, it may be advantageous to initiateadministration of a disclosed compound first, for example one or moredays or weeks prior to initiation of administration of the antiviral.Moreover, additional drugs may be given in conjunction with the abovecombination therapy.

In another embodiment, a disclosed compound may be conjugated (e.g.,covalently bound directly or through molecular linker to a free carbon,nitrogen (e.g. an amino group), or oxygen (e.g. an active ester) of adisclosed compound), with a detection moiety, e.g. a fluorophore moiety(such a moiety may for example re-emit a certain light frequency uponbinding to a virus and/or upon photon excitation. Contemplatedfluorophores include AlexaFluor® 488 (Invitrogen) and BODIPY FL(Invitrogen), as well as fluorescein, rhodamine, cyanine,indocarbocyanine, anthraquinones, fluorescent proteins, aminocoumarin,methoxycoumarin, hydroxycoumarin, Cy2, Cy3, and the like. Such disclosedcompounds conjugated to a detection moiety may be used in e.g. a methodfor detecting HBV or biological pathways of HBV infection, e.g., invitro or in vivo; and/or methods of assessing new compounds forbiological activity.

EXAMPLES

The compounds described herein can be prepared in a number of ways basedon the teachings contained herein and synthetic procedures known in theart. In the description of the synthetic methods described below, it isto be understood that all proposed reaction conditions, including choiceof solvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, can be chosen to be the conditionsstandard for that reaction, unless otherwise indicated. It is understoodby one skilled in the art of organic synthesis that the functionalitypresent on various portions of the molecule should be compatible withthe reagents and reactions proposed. Substituents not compatible withthe reaction conditions will be apparent to one skilled in the art, andalternate methods are therefore indicated. The starting materials forthe examples are either commercially available or are readily preparedby standard methods from known materials. At least some of the compoundsidentified as “intermediates” herein are contemplated as compounds ofthe invention.

Example 1: Synthesis of Compounds Synthesis of 11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxylic acid (6): ACommon Intermediate

Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl)thio)-3-nitrobenzoate (3)

To a stirring solution of methyl 4-fluoro-3-nitrobenzoate 2 (30 g,150.67 mmol) in DMF (300 mL) under inert atmosphere were added cesiumcarbonate (58.76 g, 180.8 mmol) and methyl 2-mercaptobenzoate 1 (22.6mL, 165.47 mmol) at RT; heated to 55-60° C. and stirred for 2 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (1500 mL) and the precipitatedsolid was filtered to obtain the crude. The crude was washed with water(500 mL), hexane (200 mL) and dried in vacuo to afford compound 3 (48.8g, 93%) as yellow solid. TLC: 20% EtOAc/hexanes (R_(f). 0.4); ¹H NMR(CDCl₃, 400 MHz): δ 8.85 (s, 1H), 7.99-7.92 (m, 2H), 7.66-7.56 (m, 3H),6.93 (d, J=8.6 Hz, 1H), 3.94 (s, 3H), 3.79 (s, 3H).

Synthesis of methyl 3-amino-4-((2-(methoxycarbonyl) phenyl) thio)benzoate (4)

To a stirring solution of compound 3 (48 g, 138.32 mmol) in MeOH (1000mL) under inert atmosphere was added 10% Pd/C (20 g, wet) at RT underhydrogen atmosphere in an autoclave (100 psi pressure) and stirred for24 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was filtered through celite, washed with50% MeOH/CH₂Cl₂ (500 mL). The filtrate was removed in vacuo to obtainthe crude which as triturated with diethyl ether (200 mL), washed withhexane (200 mL) and dried in vacuo to afford compound 4 (40 g, 91%) asyellow solid. TLC: 10% EtOAc/hexanes (R_(f): 0.3); ¹H NMR (DMSO-d₆, 400MHz): δ 7.95 (dd, J=7.8, 1.4 Hz, 1H), 7.48-7.35 (m, 3H), 7.23 (td,J=7.5, 1.1 Hz, 1H), 7.15 (dd, J=8.0, 1.8 Hz, 1H), 6.66 (dd, J=8.2, 0.8Hz, 1H), 5.67 (br s, 2H), 3.88 (s, 3H), 3.84 (s, 3H).

Synthesis of 3-amino-4-((2-carboxyphenyl) thio) benzoic acid (5)

To a stirring solution of compound 4 (40 g, 126.18 mmol) in THF:H₂O(5:1, 400 mL) was added lithium hydroxide monohydrate (26 g, 619.0 mmol)at 0° C.; warmed to RT and stirred for 48 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo. The pH of the residue was acidified with 2 N HCl to ˜2. Theprecipitated solid was filtered and dried in vacuo to afford compound 5(34.6 g, 95%) as an off-white solid. TLC: 30% EtOAc/hexanes (R_(f):0.1); ¹H NMR (DMSO-d₆, 500 MHz): δ 13.00 (br s, 2H), 7.93 (dd, J=7.7,1.0 Hz, 1H), 7.42 (s, 1H), 7.40-7.31 (m, 2H), 7.18 (t, J=7.4 Hz, 1H),7.13 (dd, J=8.0, 1.6 Hz, 1H), 6.61 (d, J=7.8 Hz, 1H), 5.55 (br s, 2H).

Synthesis of 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (6)

To a stirring solution of compound 5 (31 g, 107.26 mmol) in THF (600 mL)under inert atmosphere was added CDI (86.88 g, 536.29 mmol) at 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was acidifiedwith 2 N HCl to pH˜4. The obtained solid was filtered and further driedby using toluene (2×200 mL) to afford compound 6 (26 g, 90%) as whitesolid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ13.22 (br s, 1H), 10.81 (s, 1H), 7.78 (s, 1H), 7.72-7.64 (m, 3H),7.57-7.44 (m, 3H).

Synthesis of 7-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (13): A Common Intermediate

Synthesis of 4-((2-(methoxycarbonyl) phenyl)thio)-2-methyl-5-nitrobenzoic acid (10)

To a stirring solution of methyl 2-mercaptobenzoate 1 (514 mg, 3.08mmol) in DMF (10 mL) under inert atmosphere were added cesium carbonate(1.81 g, 5.57 mmol), compound 8 (560 mg, 2.78 mmol) at RT; heated to 60°C. and stirred for 4 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed under reducedpressure. The residue was diluted with water (20 mL) and pH was adjustedto ˜2 with 1 N HCl, filtered the precipitated solid and dried in vacuoto afford compound 10 (500 mg, 52%) as an off-white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 13.47 (br s, ¹H),8.59 (s, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.68-7.60 (m, 3H), 6.83 (s, 1H),3.72 (s, 3H), 2.40 (s, 3H).

Synthesis of methyl 3-amino-4-((2-(methoxycarbonyl) phenyl)thio)-5-methylbenzoate (11)

To a stirring solution of compound 10 (500 mg, 1.45 mmol) in THF:H₂O(2:1, 15 mL) was added lithium hydroxide monohydrate (300 mg, 7.31 mmol)at RT and stirred for 8 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. Theresidue was diluted with water (15 mL), and pH was adjusted to ˜2 with 1N HCl, filtered the precipitated solid and dried in vacuo to affordcrude compound 11 (500 mg) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂(R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 13.51 (br s, 2H), 8.57 (s,1H), 7.92 (d, J=7.2 Hz, 1H), 7.64-7.58 (m, 2H), 7.53 (t, J=8.0 Hz, 1H),6.89 (s, 1H), 2.41 (s, 3H).

Synthesis of 5-amino-4-((2-carboxyphenyl) thio)-2-methylbenzoic acid(12)

To a stirring solution of compound 11 (500 mg) in MeOH (15 mL) underinert atmosphere was added Pd/C (250 mg) at RT and stirred underhydrogen atmosphere for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo toafford crude compound 12 (430 mg) as an off-white solid. TLC:MeOH/CH₂Cl₂ (R_(f): 0.1); LC-MS: 84.24%; 304.5 (M⁺+1); (column; X-SelectCSH C-18, (50×3.0 mm, 3.5 μm); RT 3.75 min. 0.05% TFA (Aq): ACN; 0.8mL/min).

Synthesis of 7-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (13)

To a stirring solution of compound 12 (430 mg) in THF (20 mL) underinert atmosphere was added CDI (1.15 g, 7.09 mmol) at RT and stirred for18 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo and neutralized with 1 NHCl, filtered the precipitated solid and dried in vacuo to afford thecrude compound 13 (290 mg) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(R₁ 0.5); ¹H-NMR (DMSO-d₆, 500 MHz): δ 13.15 (br s, 1H), 10.68 (s, 1H),7.69-7.68 (m, 2H), 7.67-7.44 (m, 4H), 2.44 (s, 3H).

9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (20): A Common Intermediate

Synthesis of mixture of 4-fluoro-2-methyl-3-nitrobenzoic acid (8) and4-fluoro-2-methyl-5-nitrobenzoic acid (9)

To a stirring solution of 4-fluoro-2-methylbenzoic acid 7 (10 g, 64.51mmol) in acetic acid (50 mL) under inert atmosphere was added fumingnitric acid (50 mL) at RT and heated to 80° C. for 6 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with ice cold water (100 mL). The precipitate was filteredand dried in vacuo to afford mixture of compounds 8 and 9 (5.3 g, 40%)as white solid. TLC: 70% EtOAc/hexanes (R_(f): 0.4); ¹H NMR (DMSO-d₆,400 MHz): δ 13.30 (br s, 2H), 8.52 (d, J=8.0 Hz, 2H), 8.10 (dd, J=8.95.9, Hz, 1H), 7.60 (d, J=12.5 Hz, 2H), 7.56 (t, J=9.3 Hz, 1H), 2.63 (s,6H), 2.48 (s, 3H); NMR showed mixture of compounds 8 & 9 in the ratio of2:1).

Synthesis of methyl 4-fluoro-2-methyl-3-nitrobenzoate (14) and methyl4-fluoro-2-methyl-5-nitrobenzoate (15)

To a stirring solution of compound 8 & 9 (10 g) in MeOH (100 mL) underargon atmosphere was conc. sulfuric acid (20 mL) at 0° C. and heated toreflux for 48 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with water (100 mL) andextracted with EtOAc (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to affordmixture of compounds 14 & 15 (6 g) as colorless thick syrup. TLC: 30%EtOAc/hexane (R_(f): 0.5); ¹H NMR (DMSO-d₆, 500 MHz): δ 8.51 (d, J=7.8Hz, 1H), 8.09 (dd, J=8.8, 5.6 Hz, 0.5H), 7.63 (d, J=12.4 Hz, 1H), 7.58(t, J=9.1 Hz, 0.5H), 3.87 (s, 4.5H), 2.62 (s, 3H), 2.45 (s, 1.5H); NMRshowed mixture of compounds 14:15 in the ratio of 2:1).

Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl)thio)-2-methyl-3-nitrobenzoate (16) and methyl 4-((2-(methoxycarbonyl)phenyl) thio)-2-methyl-5-nitrobenzoate (17)

To a stirring solution of compounds 14 & 15 (11 g) in DMF (100 mL) underinert atmosphere were added methyl 2-mercaptobenzoate 1 (10.4 g, 61.97mmol), cesium carbonate (18.5 g, 56.81 mmol) at 0° C.; heated to 80° C.and stirred for 4 h. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was diluted with ice cold water(100 mL) and extracted with EtOAc (2×100 mL). The combined organicextracts were washed with water (200 mL), brine (200 mL), dried oversodium sulfate, filtered and concentrated in vacuo to afford mixture ofcompounds 16 & 17 (12 g) as yellow solid. TLC: 20% EtOAc/hexanes (R_(f):0.2); LC-MS: 12.57%+81.14%; 370.8 (M⁺+1); (column; X-Select CSH C18,(50×3.0 mm, 3.5 μm); RT 2.77 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); RT4.05, 4.14 min.

Synthesis of methyl 5-amino-4-((2-(methoxycarbonyl) phenyl)thio)-2-methylbenzoate (18) and Synthesis of methyl3-amino-4-((2-(methoxycarbonyl) phenyl) thio)-2-methylbenzoate (18A)

To a stirring solution of compound 16 & 17 (14 g, crude) in MeOH (500mL) under inert atmosphere was added Pd/C (1.4 g, 50% wet) at RT andstirred under hydrogen atmosphere in an autoclave (6 kg/cm² pressure)for 18 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was filtered through celite, washed withMeOH (100 mL). The filtrate was concentrated in vacuo to obtain thecrude. The crude was recrystallized with EtOH (20 mL) and furtherpurified through silica gel column chromatography column chromatographyusing 10% EtOAc/hexanes to afford compound 18 (8 g, 63%%) and 18A (3 g,30) as sticky off-white solids. TLC: 30% EtOAc/hexanes (R_(f): 0.4);

¹H NMR (DMSO-d₆, 400 MHz) (18): δ 7.94 (d, J=7.1 Hz, 1H), 7.40 (t, J=7.3Hz, 1H), 7.33-7.26 (m, 2H), 7.22 (dt, J=7.6, 1.1 Hz, 1H), 6.67 (dd,J=8.2, 0.8 Hz, 1H), 5.41 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 2.33 (s,3H).

¹H NMR (DMSO-d₆, 400 MHz) (18A): δ 7.94 (dd, J=7.8, 1.4 Hz, 1H),7.42-7.38 (m, 1H), 7.32 (s, 1H), 7.26 (s, 1H), 7.22 (td, J=7.5, 1.0 Hz,1H), 6.67 (dd, J=8.1, 0.8 Hz, 1H), 5.41 (s, 2H), 3.88 (s, 2H), 3.82 (s,3H), 2.33 (s, 3H).

Synthesis of 3-amino-4-((2-carboxyphenyl) thio)-2-methylbenzoic acid(19)

To a stirring solution of compound 18A (2 g, 6.04 mmol) in THF:H₂O (4:1,50 mL) was added lithium hydroxide monohydrate (2.5 g, 10.0 mmol) at 0°C.; warmed to RT and stirred for 48 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The residue was diluted with water (10 mL) and washed withdiethyl ether (2×50 mL). The pH of the aqueous layer was acidified with4 N HCl to ˜1. The precipitated solid was filtered and dried in vacuo toafford compound 19 (1.2 g, 66%) as white solid. TLC: 2v60% MeOH/CH₂Cl₂(R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 13.01 (br s, 2H), 7.94 (d,J=7.4 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.20 (dt,J=7.4, 6.3 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.61 (d, J=7.4 Hz, 1H), 5.25(br s, 2H), 2.27 (s, 3H).

Synthesis of 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (20)

To a stirring solution of compound 19 (2.6 g, 4.30 mmol) in THF (30 mL)under argon atmosphere was added CDI (3.5 g, 21.50 mmol) at RT; heatedto 80° C. and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. Theresidue was diluted with water (20 mL) and pH was adjusted with 4 N HClto ˜2. The obtained solid was filtered, washed with diethyl ether anddried in vacuo to obtain compound 20 (1.6 g, 67%) as an off white solid.TLC: 15% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 13.20(br s, 1H), 10.23 (s, 1H), 7.74-7.60 (m, 1H), 7.56-7.51 (m, 2H),7.50-7.42 (m, 3H), 2.47 (s, 3H).

Synthesis of 6-bromo-9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (32): A Common Intermediate

Synthesis of 5-bromo-4-fluoro-2-methylbenzoic acid (22) &3-bromo-4-fluoro-2-methylbenzoic acid (23)

To a stirring solution of 4-fluoro-2-methylbenzoic acid 7 (10 g, 64.93mmol) in H₂SO₄ (200 mL) at 0° C. under argon atmosphere was addedN-bromosuccinimide (10.40 g, 58.44 mmol) portion wise for 15 min warmedto RT and stirred for 2 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withice-cold water, the precipitated solid was filtered and dried in vacuoto afford mixture of compound 22 and 23 in the ratio of 2.5:1 (14 g) asan off-white solid. TLC: 30% EtOAc/hexanes (R_(f): 0.3); ¹H-NMR(DMSO-d₆, 400 MHz): δ 8.06 (d, J=7.4 Hz, 1H), 7.82 (dd, J=8.7, 5.9 Hz,0.4H), 7.37 (d, J=9.9 Hz, 1H), 7.30 (t, J=8.4 Hz, 0.4H), 2.62 (s, 1.2H),2.50 (s, 3H);

Synthesis of 5-bromo-4-fluoro-2-methyl-3-nitrobenzoic acid &3-bromo-4-fluoro-2-methyl-5-nitrobenzoic acid (24 & 25)

To a stirring solution of compound 22 & 23 (14 g, 60.34 mmol) insulphuric acid (70 mL) under inert atmosphere at 0° C. was added fumingnitric acid (70 mL) dropwise for 30 min at 0° C. warmed to RT andstirred for 2 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was quenched with ice-cold water (100mL). The precipitated solid was filtered, washed with water (100 mL) anddried in vacuo to afford mixture of compound 24 & 25 in the ratio of 2:1(10 g) as pale yellow solid. TLC: 30% EtOAc/hexanes (R_(f): 0.2). ¹H NMR(DMSO-d₆, 400 MHz): δ 13.86 (br s, 3H), 8.47 (d, J=7.8 Hz, 1H), 8.30 (d,J=6.9 Hz, 2H), 2.72 (s, 3H), 2.44 (s, 8H);

Synthesis of methyl 5-bromo-4-fluoro-2-methyl-3-nitrobenzoate (26) &methyl 3-bromo-4-fluoro-2-methyl-5-nitrobenzoate (26&27)

To a stirring solution of compound 24 & 25 (10 g, 35.9 mmol) in MeOH(200 mL) under inert atmosphere was added concentrated sulfuric acid (10mL) dropwise for 15 min at 0° C.; heated to reflux and stirred for 16 h.The reaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The residue was diluted with ice-coldwater (100 mL) and extracted with EtOAc (2×150 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 10% EtOAc/hexanes to afford mixture ofcompound 26 & 27 in 2:1 ratio (8 g) as an off-white solid. TLC: 10%EtOAc/hexanes (R_(f): 0.5); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.48 (d, J=7.7Hz, 0.4H), 8.33 (d, J=7.0 Hz, 1H), 3.90 (s, 1.2H), 3.88 (s, 3H), 2.69(s, 1.2H), 2.42 (s, 3H);

Synthesis of methyl 5-bromo-4-((2-(methoxycarbonyl) phenyl)thio)-2-methyl-3-nitrobenzoate (28) & methyl3-bromo-4-((2-(methoxycarbonyl) phenyl) thio)-2-methyl-5-nitrobenzoate(29)

To a stirring solution of compound 26 & 27 (8 g, 27.49 mmol) in DMF (50mL) under argon atmosphere were added methyl 2-mercaptobenzoate 1 (5.5g, 32.98 mmol), cesium carbonate (9.8 g, 30.24 mmol) at RT; heated to80° C. and stirred for 2 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted withice-cold water (150 mL). The precipitated solid was filtered, washedwith water (100 mL) and dried in vacuo to obtain the crude which wastriturated with EtOH (10 mL) & diethylether (25 mL) filtered and driedin vacuo to afford mixture of compound 28 and 29 (6 g) as pale yellowsolid. TLC: 20% EtOAc/hexanes (R_(f): 0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ8.37 (s, 1H), 8.02 (dd, J=7.8, 1.4 Hz, 1H), 7.54-7.45 (m, 1H), 7.38-7.32(m, 1H), 6.62 (d, J=7.8 Hz, 1H), 3.91 (d, J=2.8 Hz, 6H), 2.38 (s, 3H);LC-MS no ionization.

Synthesis of methyl3-amino-5-bromo-4-((2-(methoxycarbonyl)phenyl)thio)-2-methylbenzoate(30)

To a stirring solution of compound 28 & 29 (5 g, 11.39 mmol) in aceticacid (100 mL) was added iron powder (6.37 g, 113.89 mmol) at RT; heatedto reflux and stirred for 16 h. The reaction was monitored by TLC; aftercompletion, the reaction mixture was diluted with EtOAc (200 mL). Theorganic extract was dried over sodium sulfate, filtered and concentratedin vacuo to obtain the crude. The crude was triturated with EtOH (25 mL)and dried in vacuo to afford compound 30 (2.6 g, 55%) as pale yellowsolid. TLC: 20% EtOAc/hexanes (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ7.99 (dd, J=7.8, 1.4 Hz, 1H), 7.45-7.40 (m, 1H), 7.28-7.23 (m, 2H), 6.56(dd, J=8.2, 0.8 Hz, 1H), 5.77 (s, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 2.20(s, 3H); LC-MS: 97.59%; 412.1 (M+2)⁺; (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 2.84 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min).

Synthesis of 3-amino-5-bromo-4-((2-carboxyphenyl) thio)-2-methylbenzoicacid (31)

To a stirring solution of compound 30 (2 g, 4.89 mmol) in THF:H₂O (4:1,25 mL) was added lithium hydroxide monohydrate (2.1 g, 50.00 mmol)portion wise for 10 min at 0° C.; warmed to RT and stirred for 48 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo and the aqueous layer was washed withdiethylether (2×5 mL) The pH of the aqueous layer was acidified with 2 NHCl to ˜1. The precipitated solid was filtered and further dried byzoetrope using toluene (10 mL) to afford compound 31 (1.6 g 86%) as anoff-white solid. TLC: 20% EtOAc/hexane (R_(f): 0.2); ¹H-NMR (DMSO-d₆,500 MHz): δ 13.25 (br s, 2H), 7.98 (d, J=7.5 Hz, 1H), 7.38 (t, J=7.4 Hz,1H), 7.27-7.19 (m, 2H), 6.54 (d, J=8.1 Hz, 1H), 5.67 (br s, 2H), 2.23(s, 3H); LC-MS: 98.30%; 383.9 (M+2)⁺; (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 2.08 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min).

Synthesis of 6-bromo-9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (32)

To a stirring solution of compound 31 (2 g, 5.25 mmol) in THF (100 mL)under inert atmosphere was added CDI (4.4 g, 26.25 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was quenched with ice-cold-water (50mL) and washed with EtOAc (2×75 mL). The pH of the residue was adjustedto ˜2 using 1 N HCl. The precipitated solid was filtered, washed withwater (50 mL) and further dried by azeotropic distillation using tolueneto afford compound 32 (1.2 g, 63%) as an off-white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 13.44 (br s, 1H),10.36 (s, 1H), 7.78 (s, 1H), 7.70-7.64 (m, 1H), 7.56-7.51 (m, 1H),7.51-7.44 (m, 2H), 2.40 (s, 3H); LC-MS: 97.42%; 363.9 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.23 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (20): (Alternate Approach)

To a stirring solution of 6-bromo-9-methyl-11-oxo-10,11-dihydrodibenzo[b, f] [1, 4] thiazepine-8-carboxylic acid 32 (1 g, 2.75 mmol) in MeOH(20 mL) under inert atmosphere was added 10% Pd/C (1 g, 50% wet) at RTand stirred under hydrogen atmosphere at RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite and eluted with 50%MeOH/CH₂Cl₂ (2×50 mL). The filtrate was concentrated in vacuo to obtainthe crude. The crude was diluted with water (20 mL) and the obtainedsolid was filtered dried in vacuo to afford compound 20 (300 mg, 38%) asan off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (DMSO-d₆,400 MHz): δ 13.15 (br s, 1H), 10.23 (s, 1H), 7.69-7.65 (m, 1H),7.55-7.51 (m, 2H), 7.50-7.42 (m, 3H), 3.31 (s, 3H); LC-MS: 90.04%; 285.9(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.01 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 2-chloro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (40): A Common Intermediate

Synthesis of 5-chloro-2-((4-methoxybenzyl) thio) benzonitrile (35)

To a stirring solution of 5-chloro-2-fluorobenzonitrile 33 6.41 mmol) inDMF (10 mL) under inert atmosphere was added cesium carbonate (2.30 g,7.05 mmol) at RT; heated to 40° C. and to this was added(4-methoxyphenyl) methanethiol 34 (1.08 g, 7.05 mmol); heated to 60° C.and stirred for 2 h. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was diluted with water (20 mL) andextracted with EtOAc (2×25 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel column chromatographyusing 3-5% EtOAc/hexanes to afford compound 35 (1 g, 54%) as whitesolid. TLC: 10% EtOAc/hexanes (R_(f): 0.6); ¹H-NMR (CDCl₃, 500 MHz): δ7.57 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.28-7.27 (m, 1H), 7.20 (d, J=9.0Hz, 2H), 6.81 (d, J=9.0 Hz, 2H), 4.15 (s, 2H), 3.78 (s, 3H).

Synthesis of 5-chloro-2-mercaptobenzonitrile (36)

A stirred solution of compound 35 (1 g, 3.47 mmol) in trifluoro aceticacid (10 mL) under inert atmosphere was stirred at 70° C. for 5 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo to obtain the crude compound 36 (590 mg)which was carried to the next step without further purification. TLC:30% EtOAc/hexanes (R_(f): 0.2); ¹H-NMR (CDCl₃, 500 MHz): δ 7.57 (s, 1H),7.41 (d, J=9.0 Hz, 1H), 7.34 (d, J=9.0 Hz, 1H), 4.08 (s, 1H).

Synthesis of methyl 4-((4-chloro-2-cyanophenyl) thio)-3-nitrobenzoate(37)

To a stirring solution of compound 36 (620 mg, 3.11 mmol) in DMF (10 mL)under inert atmosphere was added cesium carbonate (1.1 g, 3.42 mmol) atRT; heated to 40° C. and stirred for 10 min. To this was added methyl4-fluoro-3-nitrobenzoate 2 (582 mg, 3.42 mmol) at 60° C. and stirred for3 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with water (20 mL) andextracted with EtOAc (2×20 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel column chromatographyusing 25% EtOAc/hexanes to afford compound 37 (600 mg, 55%) as paleyellow solid. TLC: 30% EtOAc/hexanes (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400MHz): δ 8.66 (s, 1H), 8.33 (s, 1H), 8.05-8.03 (m, 1H), 7.98-7.92 (m,2H), 7.02 (d, J=8.4 Hz, 1H), 3.86 (s, 3H).

Synthesis of methyl 3-amino-4-((4-chloro-2-cyanophenyl) thio) benzoate(38)

To a stirring solution of compound 37 (450 mg, 1.29 mmol) in acetic acid(15 mL) under inert atmosphere was added iron powder (724 mg, 12.9 mmol)at RT; heated to 90° C. and stirred for 3 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo. The residue was basified with saturated NaHCO₃ solution (15 mL)and extracted with CH₂Cl₂ (2×20 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was triturated with 3% EtOAc/hexanes (2×5 mL) toafford compound 38 (290 mg, 70%) as pale yellow solid. TLC: 20%MeOH/CH₂Cl₂ (R_(f): 0.7); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.05 (s, ¹H),7.63-7.60 (m, 1H), 7.48 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.8Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 5.88 (s, 2H), 3.84 (s, 3H).

Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-5-chlorobenzoic acid(39)

To a stirring solution of compound 38 (450 mg, 1.41 mmol) in MeOH (10mL) was added potassium hydroxide (792 mg, 14.1 mmol) in water (3 mL) at0° C.; heated to 90° C. and stirred for 9 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo. The residue was acidified with 1 N HCl to pH˜4.0. The obtainedsolid was filtered, washed with ether (2×5 mL) and dried in vacuo toafford compound 39 (350 mg, 76%) as an off-white solid. TLC: 20%MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H-NMR (DMSO-d₆, 400 MHz): δ 12.92 (br s, 2H),7.89 (s, 1H), 7.44-7.38 (m, 3H), 7.14 (d, J=8.8 Hz, 1H), 6.60 (d, J=8.8Hz, 1H), 5.64 (br s, 2H).

Synthesis of 2-chloro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (40)

To a stirring solution of compound 39 (30 mg, 0.09 mmol) in THF (2 mL)under inert atmosphere was added CDI (45 mg, 0.27 mmol) at RT andstirred for 7 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasacidified with 2 N HCl to pH˜4.0. The obtained solid was filtered,washed with ether (2×3 mL) and dried in vacuo to afford compound 40 (15mg, 53%) as an off-white solid. TLC: 15% MeOH/CH₂Cl₂ (R_(f): 0.5);¹H-NMR (DMSO-d₆, 400 MHz): δ 13.05 (br s, 1H), 10.98 (s, 1H), 7.80 (s,1H), 7.72-7.70 (m, 3H), 7.64 (s, 2H).

Synthesis of 3-chloro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (47): A Common Intermediate

Synthesis of 4-chloro-2-((4-methoxybenzyl) thio) benzonitrile (42)

To a stirring solution of 4-chloro-2-fluorobenzonitrile 41 (1 g, 6.41mmol) in DMF (25 mL) under inert atmosphere was added cesium carbonate(2.30 g, 7.05 mmol) at RT; heated to 40° C. and to this was added(4-methoxyphenyl) methanethiol 34 (1.08 g, 7.05 mmol); heated to 60° C.and stirred for 2 h. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was diluted with water (20 mL) andextracted with EtOAc (2×25 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel column chromatographyusing 4% EtOAc/hexanes to afford compound 42 (900 mg, 48%) as whitesolid. TLC: 10% EtOAc/hexanes (R_(f): 0.6); ¹H-NMR (CDCl₃, 400 MHz): δ7.51 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 7.23-7.20 (m, 3H), 6.84 (d, J=8.4Hz, 2H), 4.19 (s, 2H), 3.79 (s, 3H).

Synthesis of 4-chloro-2-mercaptobenzonitrile (43)

A stirred solution of compound 42 (900 mg, 3.11 mmol) in trifluoroacetic acid (10 mL) under inert atmosphere at RT was heated to 70° C.and stirred for 4 h. The reaction was monitored by TLC; after completionof the reaction, the volatiles were removed in vacuo to obtain the crudecompound 43 (527 mg) as brown solid. The crude was carried to the nextstep without further purification. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.1);¹H-NMR (CDCl₃, 400 MHz): δ 7.52 (d, J=8.4 Hz, 1H), 7.41 (s, 1H),7.22-7.19 (m, 1H), 4.13 (s, 1H).

Synthesis of methyl 4-((5-chloro-2-cyanophenyl) thio)-3-nitrobenzoate(44)

To a stirring solution of compound 43 (550 mg, 2.76 mmol) in DMF (15 mL)under inert atmosphere was added cesium carbonate (988 mg, 3.04 mmol) atRT; heated to 40° C. and stirred for 10 min. To this was added methyl4-fluoro-3-nitrobenzoate 2 (515 mg, 3.04 mmol) at 60° C. and stirred for3 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with water (20 mL). Theobtained solid was filtered, washed with 15% EtOAc/hexanes (2×5 mL) anddried in vacuo to afford compound 44 (700 mg, 73%) as yellow solid. TLC:20% EtOAc/hexanes (R_(f): 0.3); ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.69 (s,1H), 8.18-8.15 (m, 2H), 8.10 (d, J=8.5 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H),7.10 (d, J=9.0 Hz, 1H), 3.90 (s, 3H).

Synthesis of methyl 3-amino-4-((5-chloro-2-cyanophenyl) thio) benzoate(45)

To a stirring solution of compound 44 (700 mg, 2.01 mmol) in acetic acid(15 mL) under inert atmosphere was added iron powder (1.12 g, 20.11mmol) at RT; heated to 90° C. and stirred for 5 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The residue was basified with 10% NaHCO₃ solution (20mL) and extracted with CH₂Cl₂ (2×30 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 20% EtOAc/hexanes to afford compound 45 (500 mg,78%) as yellow solid. TLC: 30% EtOAc/hexanes (R_(f): 0.8); ¹H-NMR(DMSO-d₆, 500 MHz): δ 7.92 (d, J=7.5 Hz, 1H), 7.51-7.43 (m, 3H), 7.17(d, J=8.0 Hz, 1H), 6.66 (s, 1H), 5.96 (s, 2H), 3.86 (s, 3H).

Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-4-chlorobenzoic acid(46)

To a stirring solution of compound 45 (500 mg, 1.57 mmol) in MeOH (6 mL)was added potassium hydroxide (1.32 mg, 23.5 mmol) in water (6 mL) at 0°C.; heated to 90° C. and stirred for 24 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The residue was diluted with water (20 mL) and extracted withEtOAc (2×25 mL). The aqueous layer was acidified with 1 N HCl to pH˜6.0.The obtained solid was filtered, washed with ether (2×7 mL) and dried invacuo to afford compound 46 (375 mg, 74%) as an off-white solid. TLC:20% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (CDCl₃, 400 MHz): δ 8.05 (d, J=8.4Hz, 1H), 7.55-7.47 (m, 3H), 7.17-7.14 (m, 1H), 6.67 (s, 1H).

Synthesis of 3-chloro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (47)

To a stirring solution of compound 46 (375 mg, 1.16 mmol) in THF (10 mL)under inert atmosphere was added CDI (564 mg, 3.48 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with water (15 mL) and acidified with 6 N HCl to pH˜1.0. Theobtained solid was filtered, washed with ether (2×5 mL) and dried invacuo to afford compound 47 (285 mg, 81%) as an off-white solid. TLC:20% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 14.56 (br s,2H), 10.90 (s, 1H), 9.11 (s, 1H), 7.71-7.65 (m, 4H).

Synthesis of 1-fluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (54): A Common Intermediate

Synthesis of methyl 2-fluoro-6-((4-methoxybenzyl) thio) benzoate (49)

To a stirring solution of methyl 2, 6-difluorobenzoate 48 (10 g, 58.13mmol) in DMF (100 mL) under inert atmosphere were added(4-methoxyphenyl) methanethiol 34 (8.96 g, 58.13 mmol), cesium carbonate(20.8 g, 63.95 mmol) at 0° C.; warmed to 10° C. and stirred for 2 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (200 mL) and extracted withEtOAc (2×800 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 10-15%EtOAc/hexanes to afford compound 49 (7.5 g, 42%) as white solid. TLC:10% EtOAc/hexanes (R_(f): 0.3); ¹H NMR (DMSO-d₆, 400 MHz) δ 7.53-7.44(m, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.6 Hz, 2H), 7.15 (t, J=9.0Hz, 1H), 6.86 (d, J=8.7 Hz, 2H), 4.22 (s, 2H), 3.72 (s, 3H), 3.33 (s,3H).

Synthesis of methyl 2-fluoro-6-mercaptobenzoate (50)

A stirred solution of compound 49 (7.5 g, 24.5 mmol) in trifluoro aceticacid (100 mL) at RT under inert atmosphere was heated to 60-65° C. andstirred for 5 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed and dried in vacuo to obtaincompound 50 (4.6 g) as brown syrup. The crude was carried forward fornext step without further purification. TLC: 10% EtOAc/hexanes (R_(f):0.7).

Synthesis of methyl 2-fluoro-6-((4-(methoxycarbonyl)-2-nitrophenyl)thio) benzoate (51)

To a stirring solution of methyl 4-fluoro-3-nitrobenzoate 2 (4.5 g,22.61 mmol) in DMF (100 mL) under inert atmosphere were added compound50 (4.6 g, crude), cesium carbonate (11 g, 33.91 mmol) at RT; heated to60-65° C. and stirred for 2 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(600 mL) and stirred for 1 h. The precipitated solid was filtered,titurated with 10% EtOAc/hexanes (2×20 mL) and dried in vacuo to affordcompound 51 (7 g, 85%) as yellow solid. TLC: 20% EtOAc/hexanes (R_(f):0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ 8.65 (s, 1H), 8.08 (dd, J=8.6, 1.9Hz, 1H), 7.79-7.72 (m, 1H), 7.67-7.61 (m, 2H), 7.01 (d, J=8.6 Hz, 1H),3.88 (s, 3H), 3.72 (s, 3H).

Synthesis of methyl 2-((2-amino-4-(methoxycarbonyl) phenyl)thio)-6-fluorobenzoate (52)

To a stirring solution of compound 51 (7.09 g, 19.17 mmol) in MeOH (200mL) under inert atmosphere was added 10% Pd/C (3.5 g) at RT and stirredunder hydrogen at 80 psi for 16 h in an autoclave. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas filtered through celite and washed with 40% MeOH/CH₂Cl₂ (3×500 mL).The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude compound wastriturated with 20% EtOAc/hexanes (200 mL) and dried in vacuo to affordcompound 52 (5 g, 78%) as an off-white solid. TLC: 20% EtOAc/hexanes(R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 7.45-7.36 (m, 3H), 7.19-7.11(m, 2H), 6.68 (d, J=7.7 Hz, 1H), 5.71 (s, 2H), 3.90 (s, 3H), 3.83 (s,3H).

Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-6-fluorobenzoic acid(53)

To a stirring solution of compound 52 (5 g, 14.92 mmol) in THF:H₂O (5:1,90 mL) was added lithium hydroxide monohydrate (3.13 g, 74.62 mmol) atRT and stirred for 16 h and heated to 80° C. for 5 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The residue was diluted with water (200 mL) andacidified with 2 N HCl to pH˜4. The precipitated solid was filtered anddried in vacuo to afford compound 53 (4 g, 87%) as an off-white solid.TLC: 30% EtOAc/hexanes (R_(f): 0.1); ¹H NMR (DMSO-d₆, 400 MHz): δ 12.89(br s, 1H), 7.42-7.36 (m, 2H), 7.35-7.31 (m, 1H), 7.14-7.08 (m, 2H),6.63 (d, J=8.0 Hz, 1H), 5.75 (br s, 2H).

Synthesis of 1-fluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (54)

To a stirring solution of compound 53 (4 g, 13.02 mmol) in THF (100 mL)under inert atmosphere was added CDI (10.56 g, 65.1 mmol) at RT andstirred for 26 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with ice cold water (80 mL) and acidified with 2 N HCl to pH˜4.The precipitated solid was filtered and dried in vacuo to affordcompound 54 (3.3 g, 88%) as an off-white solid. TLC: 15% MeOH/CH₂Cl₂(R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 13.33 (br s, 2H), 11.00 (s,1H), 7.77 (s, 1H), 7.69-7.67 (m, 2H), 7.53-7.47 (m, 1H), 7.42-7.39 (m,1H), 7.35-7.29 (m, 1H).

Synthesis of 2-fluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (61): A Common Intermediate

Synthesis of methyl-5-fluoro-2-((4-methoxybenzyl) thio) benzoate (56)

To a stirring solution of methyl 2, 5-difluorobenzoate 55 (1 g, 5.80mmol) in DMF (20 mL) under argon atmosphere were added (4-methoxyphenyl)methanethiol 34 (985 mg, 6.39 mmol), cesium carbonate (2.07 g, 6.39mmol) at RT and stirred for 3 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (30 mL) and extracted with CH₂Cl₂ (2×30 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 5-7% EtOAc/hexanes to afford compound 56(700 mg, 40%) as white solid. TLC: 10% EtOAc/hexanes (R_(f): 0.3);¹H-NMR (CDCl₃, 400 MHz): δ 7.64-7.61 (m, 1H), 7.32-7.29 (m, 3H),7.17-7.09 (m, 1H), 6.86-6.82 (m, 2H), 4.09 (s, 2H), 3.90 (s, 3H), 3.79(s, 3H).

Synthesis of methyl 5-fluoro-2-mercaptobenzoate (57)

A stirred solution of compound 56 (700 mg, 2.28 mmol) in trifluoroacetic acid (7 mL) at RT under argon atmosphere was heated to 60-65° C.and stirred for 5 h. The reaction was monitored by TLC; after completionof the reaction, the volatiles were removed and dried in vacuo to obtaincompound 57 (380 mg, 89%) as brown syrup. TLC: 10% EtOAc/hexanes (R_(f):0.7); ¹H-NMR (DMSO-d₆, 400 MHz): δ 7.70-7.58 (m, 2H), 7.42-7.35 (m, 1H),5.42 (s, 1H), 3.86 (s, 3H).

Synthesis of methyl 5-fluoro-2-((4-(methoxycarbonyl)-2-nitrophenyl)thio) benzoate (58)

To a stirring solution of methyl 4-fluoro-3-nitrobenzoate 2 (350 mg,1.75 mmol) in DMF (10 mL) under argon atmosphere were added compound 57(360 mg, 1.93 mmol), cesium carbonate (1.14 g, 3.51 mmol) at RT; heatedto 60-65° C. and stirred for 2 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (30 mL) and extracted with CH₂Cl₂ (2×40 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 7-10% EtOAc/hexanes to afford compound 58(500 mg, 78%) as yellow solid. TLC: 10% EtOAc/hexanes (R_(f): 0.3);¹H-NMR (DMSO-d₆, 400 MHz): δ 8.64 (s, 1H), 8.04-8.02 (m, 1H), 7.83-7.79(m, 2H), 7.64-7.59 (m, 1H), 7.01 (d, J=8.4 Hz, 1H), 3.88 (s, 3H), 3.71(s, 3H).

Synthesis of methyl 2-((2-amino-4-(methoxycarbonyl) phenyl)thio)-5-fluorobenzoate (59)

To a stirring solution of compound 58 (500 mg, 1.36 mmol) in MeOH (10mL) under argon atmosphere was added 10% Pd/C (300 mg) at RT and stirredunder hydrogen atmosphere (balloon pressure) for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas filtered through celite and washed with 20% MeOH/CH₂Cl₂ (2×30 mL).The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 8-10% EtOAc/hexanes toafford compound 59 (300 mg, 66%) as pale yellow solid. TLC: 30%EtOAc/hexanes (R_(f): 0.5); ¹H-NMR (DMSO-d₆, 400 MHz): δ 7.78 (d, J=9.6Hz, 1H), 7.45-7.41 (m, 2H), 7.35-7.30 (m, 1H), 7.14 (d, J=9.6 Hz, 1H),6.68-6.65 (m, 1H), 5.70 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H).

Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-5-fluorobenzoic acid(60)

To a stirring solution of compound 59 (300 mg, 0.89 mmol) in THF:H₂O(5:1, 6 mL) under argon atmosphere was added lithium hydroxidemonohydrate (188 mg, 4.47 mmol) at RT and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the volatileswere removed in vacuo. The residue was diluted with water (15 mL) andacidified with 6 N HCl to pH˜4. The precipitated solid was filtered anddried in vacuo to afford compound 60 (180 mg, 66%) as white solid. TLC:50% EtOAc/hexanes (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 12.99-12.96(m, 2H), 7.69 (d, J=6.8 Hz, 1H), 7.40 (t, J=7.2 Hz, 2H), 7.29 (t, J=7.2Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 6.64-6.61 (m, 1H), 5.64-5.61 (m, 2H).

Synthesis of 2-fluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (61): A Common Intermediate

To a stirring solution of compound 60 (180 mg, 0.58 mmol) in THF (10 mL)under argon atmosphere was added CDI (284 mg, 1.75 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with ice cold water (10 mL) and acidified with 6 N HCl to pH˜4.The precipitated solid was filtered and dried in vacuo to affordcompound 61 (80 mg, 47%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 13.30 (br s, 1H), 10.93 (s,1H), 7.70 (s, 1H), 7.67 (d, J=7.6 Hz, 2H), 7.59 (t, J=7.6 Hz, 1H), 7.48(t, J=7.6 Hz, 1H), 7.40-7.35 (m, 1H).

Synthesis of 3-fluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (68): A Common Intermediate

Synthesis of methyl 4-fluoro-2-((4-methoxybenzyl) thio) benzoate (63)

To a stirring solution of methyl 2-bromo-4-fluorobenzoate 62 (2 g, 8.58mmol) in 1,4-dioxane (50 mL) under inert atmosphere were added(4-methoxyphenyl) methanethiol 34 (1.58 g, 10.25 mmol), cesium carbonate(4.18 g, 12.80 mmol) at RT and purged under argon atmosphere for 30 min.To this was added Pd(dppf)₂Cl₂ (306 mg, 0.42 mmol); heated to 120° C.and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(20 mL) and extracted with EtOAc (2×250 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 7% EtOAc/hexanes to afford compound 63 (1.6g, 61%) as an off-white solid. TLC: 10% EtOAc/hexanes (R_(f): 0.4); ¹HNMR (CDCl₃, 400 MHz): δ 8.01 (dd, J=8.7, 6.2 Hz, 1H), 7.34 (d, J=7.9 Hz,2H), 7.04 (dd, J=10.3, 2.4 Hz, 1H), 6.88-6.80 (m, 3H), 4.09 (s, 2H),3.88 (s, 3H), 3.80 (s, 3H).

Synthesis of methyl 4-fluoro-2-mercaptobenzoate (64)

A stirred solution of compound 63 (2.2 g, 7.18 mmol) in trifluoro aceticacid (30 mL) at RT under inert atmosphere was heated to 90° C. andstirred for 3 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo to obtain compound 64(1.33 g, crude) as brown syrup. The crude was carried forward for nextstep without further purification. TLC: 10% EtOAc/hexanes (R_(f): 0.8).

Synthesis of methyl 4-fluoro-2-((4-(methoxycarbonyl)-2-nitrophenyl)thio) benzoate (65)

To a stirring solution of methyl 4-fluoro-3-nitrobenzoate 2 (1.29 g,6.93 mmol) in DMF (50 mL) under inert atmosphere were added cesiumcarbonate (2.93 g, 9.01 mmol) and compound 64 (1.2 g, 6.03 mmol) at RT;heated to 55-60° C. and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith water (20 mL), the precipitated solid was filtered to obtain thecrude. The crude was washed with pentane (2×20 mL) and dried in vacuo toafford compound 65 (1.5 g, 68%) as yellow solid. TLC: 10% EtOAc/hexanes(R_(f): 0.3); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.63 (s, 1H), 8.13-8.04 (m,2H), 7.53-7.46 (m, 2H), 7.24 (d, J=8.4 Hz, 1H), 3.89 (s, 3H), 3.72 (s,3H).

Synthesis of 2-((4-carboxy-2-nitrophenyl) thio)-4-fluorobenzoic acid(66)

To a stirring solution of compound 65 (1.5 g, 4.10 mmol) in THF:H₂O(4:1, 20 mL) was added lithium hydroxide monohydrate (690 mg, 16.4 mmol)at RT, heated to 80° C. and stirred for 2 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo. The pH of the residue was acidified with 2 N HCl to 6. Theprecipitated solid was filtered and dried in vacuo to afford compound 66(1.2 g, 86%) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2);¹H-NMR (DMSO-d₆, 400 MHz): δ 13.46 (br s, 2H), 8.58 (s, 1H), 8.08-8.01(m, 2H), 7.45-7.40 (m, 1H), 7.38-7.35 (m, 1H), 7.29 (d, J=8.4 Hz, 1H).

Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-4-fluorobenzoic acid(67)

To a stirring solution of compound 66 (1.2 g, 3.56 mmol) in MeOH (50 mL)under inert atmosphere was added 10% Pd/C (300 mg) at RT and stirredunder hydrogen atmosphere (balloon pressure) for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas filtered through celite, washed with MeOH (20 mL). The filtrate wasremoved in vacuo to obtain the crude which as triturated with 10%EtOAc/n-pentane (50 mL) to afford compound 67 (1 g, 91%) as an off-whitesolid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H-NMR (DMSO-d₆, 400 MHz): δ12.96 (br s, 2H), 8.06-8.02 (m, 1H), 7.46 (s, 1H), 7.40 (d, J=8.0 Hz,1H), 7.16 (d, J=8.0 Hz, 1H), 7.07-7.02 (m, 1H), 6.24 (d, J=8.0 Hz, 1H),5.67 (br s, 2H).

Synthesis of 3-fluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (68)

To a stirring solution of compound 67 (1 g, 3.25 mmol) in THF (30 mL)under inert atmosphere was added CDI (1.61 g, 9.77 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was acidified with 2 N HCl to pH˜4.The obtained solid was filtered, washed with water (20 mL), ether (2×5mL) and dried in vacuo to afford compound 68 (760 mg, 80%) as whitesolid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H-NMR (DMSO-d₆, 400 MHz): δ13.24 (br s, 1H), 10.83 (s, 1H), 7.78-7.74 (m, 2H), 7.69-7.66 (m, 2H),7.47-7.44 (m, 1H), 7.35-7.30 (m, 1H).

Synthesis of 4-fluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (76): A Common Intermediate

Synthesis of methyl 2, 3-difluorobenzoate (70)

To a stirring solution of 2, 3-difluorobenzoic acid 69 (1 g, 6.28 mmol)in MeOH (10 mL) under inert atmosphere was added Conc. H₂SO₄ (5 mL) at0° C. and heated to reflux for 36 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The residue was diluted with water (25 mL) and pH adjusted to ˜8 withsaturated sodium bicarbonate solution (20 mL) and extracted with EtOAc(2×20 mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 20%EtOAc/hexanes to afford compound 70 (800 mg, 74%) as an off-white solid.TLC: 40% EtOAc/hexanes (R_(f): 0.8); ¹H NMR (DMSO-d₆, 500 MHz) δ7.80-7.65 (m, 2H), 7.41-7.23 (m, 1H), 3.88 (s, 3H).

Synthesis of methyl 3-fluoro-2-((4-methoxybenzyl) thio) benzoate (71)

To a stirring solution of compound 70 (800 mg, 4.65 mmol) in DMF (10 mL)under inert atmosphere were added (4-methoxyphenyl) methanethiol 34 (282mg, 5.11 mmol), cesium carbonate (1.66 g, 5.11 mmol) at RT and stirredfor 6 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted water (25 mL) and extractedwith ether (2×40 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using20% EtOAc/hexanes to afford compound 71 (750 mg, 53%) as an off-whitesolid. TLC: 20% EtOAc/hexanes (R_(f): 0.4); ¹H NMR (DMSO-d₆, 500 MHz): δ7.49-7.36 (m, 3H), 7.10 (d, J=8.9 Hz, 2H), 6.79 (d, J=8.9 Hz, 2H), 4.06(s, 2H), 3.81 (s, 3H), 3.70 (s, 3H);

Synthesis of methyl 3-fluoro-2-mercaptobenzoate (72)

A stirred solution of compound 71 (750 mg, 2.45 mmol) in trifluoroacetic acid (7 mL) at RT under inert atmosphere was heated to 70° C. andstirred for 2 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo to obtain compound 72(1.1 g, crude) as colorless liquid. The crude was carried forward fornext step. TLC: 30% EtOAc/hexanes (R_(f): 0.8).

Synthesis of methyl 3-fluoro-2-((4-(methoxycarbonyl)-2-nitrophenyl)thio) benzoate (73)

To a stirring solution of compound 72 (5.96 g, 3.20 mmol) in DMF (100mL) under inert atmosphere were added methyl 4-fluoro-3-nitrobenzoate 2(5.8 g, 2.91 mmol), cesium carbonate (10.41 g, 3.20 mmol) at RT; heatedto 80° C. and stirred for 4 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with icecold water (25 mL). The obtained solid was filtered, washed with hexane(2×10 mL) and dried in vacuo to afford compound 73 (7.8 g, 73%) as anpale yellow solid. TLC: 30% EtOAc/hexanes (R_(f): 0.5); ¹H NMR (DMSO-d₆,500 MHz): δ 8.67 (s, 1H), 8.05 (dd, J=8.7, 1.7 Hz, 1H), 7.94-7.75 (m,2H), 7.73-7.67 (m, 1H), 7.00 (d, J=8.4 Hz, 1H), 3.88 (s, 3H), 3.77-3.64(m, 3H).

Synthesis of methyl 2-((2-amino-4-(methoxycarbonyl) phenyl)thio)-3-fluorobenzoate (74)

To a stirring solution of compound 73 (670 mg, 1.83 mmol) in MeOH (10mL) under inert atmosphere was added 10% Pd/C (150 mg) at RT and stirredunder hydrogen atmosphere (balloon pressure) for 12 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas filtered through celite and the filtrate was concentrated in vacuoto afford compound 74 (500 mg, 81%) as an off-white solid. TLC: 30%EtOAc/hexanes (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 7.58-7.50 (m,2H), 7.48-7.41 (m, 1H), 7.33 (s, 1H), 7.04 (s, 2H), 5.59 (br s, 2H),3.82 (s, 3H), 3.79 (s, 3H).

Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-3-fluorobenzoic acid(75)

To a stirring solution of compound 74 (500 mg, 1.49 mmol) in THF:H₂O(4:1, 20 mL) was added lithium hydroxide monohydrate (376 mg, 8.95 mmol)at RT; heated to 80° C. and stirred for 3 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo. The residue was diluted with water (25 mL) and washed withdiethyl ether (2×25 mL). The aqueous layer was acidified with 2 N HCl topH˜4 and extracted with EtOAc (2×20 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude which was washed with diethyl ether (2×5 mL) and driedin vacuo to afford compound 75 (300 mg, 65%) as an off-white solid. TLC:10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (DMSO-d₆, 500 MHz): δ 12.68 (br s,2H), 7.54-7.45 (m, 2H), 7.39-7.32 (m, 1H), 7.28 (s, 1H), 7.09-7.06 (m,1H), 7.02-6.96 (m, 1H), 5.56 (br s, 2H);

Synthesis of 4-fluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (76)

To a stirring solution of compound 75 (300 mg, 0.97 mmol) in THF (15 mL)under inert atmosphere was added CDI (474 mg, 2.92 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The pH of the residuewas acidified with 4 N HCl to ˜2. The obtained solid was filtered,washed with diethyl ether (2×5 mL) and dried in vacuo to afford compound76 (150 mg, 53%) as an off-white solid. TLC: 15% MeOH/CH₂Cl₂ (R_(f):0.5); ¹H NMR (DMSO-d₆ 400 MHz): δ 13.38 (br s, 1H), 10.92 (s, 1H), 7.79(s, 1H), 7.75-7.66 (m, 2H), 7.55-7.46 (m, 3H).

Synthesis of 7-fluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (81): A Common Intermediate

Synthesis of methyl 2-fluoro-4-((2-(methoxycarbonyl) phenyl)thio)-5-nitrobenzoate (78)

To a stirring solution of methyl 2, 4-difluoro-5-nitrobenzoate 77 (9.0g, 41.45 mmol) in DMF (100 mL) under inert atmosphere were added methyl2-mercaptobenzoate 1 (6.97 g, 41.45 mmol), cesium carbonate (14.82 g,45.60 mmol) at 0° C.; warmed to 10° C. and stirred for 2 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with water (800 mL) and extracted with EtOAc (2×500mL). The combined organic extracts were dried under sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 10%EtOAc/hexanes to afford compound 78 (11 g, 73%) as an off-white solid.TLC: 10% EtOAc/hexanes (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 8.69(d, J=6.8 Hz, 1H), 8.04-7.92 (m, 1H), 7.81-7.69 (m, 3H), 6.60 (d, J=11.5Hz, 1H), 3.88 (s, 3H), 3.73 (s, 3H).

Synthesis of methyl 5-amino-2-fluoro-4-((2-(methoxycarbonyl) phenyl)thio) benzoate (79)

To a stirring solution of compound 78 (11 g, 30.13 mmol) in MeOH (400mL) under inert atmosphere was added 10% Pd/C (5 g) at RT and stirredunder hydrogen atmosphere (balloon pressure) for 24 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas filtered through celite, washed with 30% MeOH/CH₂Cl₂ (3×60 mL). Thefiltrate was removed in vacuo to afford compound 79 (6.5 g, 64%) as anoff-white solid. TLC: 20% EtOAc/hexanes (R_(f): 0.4); ¹H NMR (DMSO-d₆,400 MHz): δ 8.01-7.88 (m, 1H), 7.45-7.40 (m, 1H), 7.34-7.24 (m, 3H),6.72 (dd, J=8.2, 0.8 Hz, 1H), 5.51 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H).

Synthesis of 5-amino-4-((2-carboxyphenyl) thio)-2-fluorobenzoic acid(80)

To a stirring solution of compound 79 (6.5 g, 19.4 mmol) in THF:H₂O(4:1, 90 mL) was added lithium hydroxide monohydrate (4 g, 97.01 mmol)at RT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. The pHof the residue was acidified with 2 N HCl to ˜4. The precipitated solidwas filtered and dried in vacuo to afford compound 80 (4.5 g, 75.6%) asan off-white solid. TLC: 30% EtOAc/hexane (R_(f): 0.2); ¹H NMR (DMSO-d₆,400 MHz): δ 13.19 (br s, 2H), 7.96 (dd, J=7.7, 1.5 Hz, 1H), 7.39 (t,J=7.3 Hz, 1H), 7.30 (d, J=6.6 Hz, 1H), 7.27-7.20 (m, 2H), 6.68 (dd,J=8.2, 0.7 Hz, 1H), 5.42 (br s, 2H).

Synthesis of 7-fluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (81)

To a stirring solution of compound 80 (4.5 g, 14.65 mmol) in THF (100mL) under inert atmosphere was added CDI (11.88 g, 73.28 mmol) at 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was quenched with2 N HCl to pH˜4; the precipitated solid was filtered, dried in vacuo toafford compound 81 (3.5 g, 83%) as an off-white solid. TLC: 15%MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 13.61 (br s, 1H),10.75 (s, 1H), 7.74-7.65 (m, 2H), 7.59-7.45 (m, 4H).

Synthesis of 7, 9-difluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (88): A Common Intermediate

Synthesis of 2, 4, 6-trifluoro-3-nitrobenzoic acid (83)

To 2, 4, 6-trifluorobenzoic acid 82 (15 g, 85.22 mmol) at 0° C., fumingnitric acid (20 mL) was added dropwise for 10 min; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with ice cold water (500mL) and extracted with EtOAc (2×200 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toafford compound 83 (20 g) as pale yellow liquid. TLC: 5%MeOH/CH₂Cl₂+0.05 mL CH₃COOH (R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ14.12 (br s, 1H), 7.83 (td, J=10.5, 2.1 Hz, 1H).

Synthesis of methyl 2, 4, 6-trifluoro-3-nitrobenzoate (84)

To a stirring solution of compound 83 (20 g) in MeOH (200 mL) underargon atmosphere was added concentrated sulfuric acid (20 mL) dropwisefor 20 min at 0° C. and heated to reflux for 48 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The residue was diluted with water (500 mL) andextracted with EtOAc (4×200 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 5-8% EtOAc/hexanes to afford compound 84 (14 g, 70%for 2 steps) as pale yellow syrup. TLC: 20% EtOAc/hexane (R_(f): 0.8);¹H NMR (DMSO-d₆, 400 MHz): δ 7.88 (td, J=10.6, 2.2 Hz, 1H), 3.93 (s,3H).

Synthesis of methyl 2, 6-difluoro-4-((2-(methoxycarbonyl) phenyl)thio)-3-nitrobenzoate (85)

To a stirring solution of compounds 84 (14 g, 59.57 mmol) in DMF (300mL) under inert atmosphere were added methyl 2-mercaptobenzoate 1 (11.1g, 66.07 mmol), cesium carbonate (38.77 g, 119.14 mmol) at 0° C.; warmedto RT and stirred for 2 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with icecold water (200 mL) and extracted with EtOAc (3×300 mL). The combinedorganic extracts were washed with water (200 mL), brine (200 mL), driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel column chromatographyto afford compound 85 (14.5 g, 64%) as yellow syrup. TLC: 10%EtOAc/hexanes (R_(f): 0.2); ¹H NMR (DMSO-d₆, 500 MHz): δ 7.98 (dd,J=7.7, 1.3 Hz, 1H), 7.66-7.61 (m, 1H), 7.59-7.55 (m, 1H), 7.46 (d, J=7.8Hz, 1H), 7.19 (d, J=9.3 Hz, 1H), 3.93 (s, 3H), 3.81 (s, 3H).

Synthesis of methyl 3-amino-2, 6-difluoro-4-((2-(methoxycarbonyl)phenyl) thio) benzoate (86)

To a stirring solution of compound 85 (18 g, 46.99) in MeOH (400 mL)under inert atmosphere was added Pd/C (9 g, 50% wet) at RT and stirredunder hydrogen atmosphere in an autoclave (5 kg/cm² pressure) for 16 h.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite, washed with MeOH (500 mL).The filtrate was concentrated in vacuo to afford compound 86 (15.1 g,91%) as colorless semi solid. TLC: 20% EtOAc/hexanes (R_(f): 0.5); ¹HNMR (DMSO-d₆, 500 MHz): δ 8.00-7.93 (m, 1H), 7.48-7.42 (m, 1H),7.31-7.21 (m, 2H), 6.76-6.64 (m, 1H), 5.54-5.47 (m, 2H), 3.91 (s, 3H),3.89 (s, 3H).

Synthesis of 3-amino-4-((2-carboxyphenyl) thio)-2, 6-difluorobenzoicacid (87)

To a stirring solution of compound 86 (15.1 g, 39.42 mmol) in THF:H₂O(4:1, 250 mL) was added lithium hydroxide monohydrate (8.3 g, 197.61mmol) at RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo,diluted with water (100 mL) and washed with EtOAc (2×100 mL). The pH ofthe aqueous layer was acidified with 4 N HCl to ˜4. The precipitatedsolid was filtered, washed with water (100 mL), pentane (100 mL). Theobtained solid was further dried using toluene (150 mL) to affordcompound 87 (11 g, 79%) as an off-white solid. TLC: 20% EtOAc/hexanes(R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 13.24 (br s, 1H), 7.97 (dd,J=7.7, 1.4 Hz, 1H), 7.46-7.39 (m, 1H), 7.28-7.19 (m, 2H), 6.66 (d, J=8.2Hz, 1H), 5.39 (br s, 2H).

Synthesis of 7, 9-difluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (88)

To a stirring solution of compound 87 (10 g, 30.76 mmol) in THF (200 mL)under argon atmosphere was added CDI (14.9 g, 81.97 mmol) at RT andstirred for 24 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with water (300 mL) and the pH was adjusted to ˜3 with 2 N HCl.The obtained solid was filtered, washed with water (100 mL), pentane (50mL) and diethyl ether (150 mL) and dried in vacuo to obtain compound 88(2.83 g, 30%) as brick red solid. TLC: 15% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹HNMR (DMSO-d₆, 500 MHz): δ 14.19 (br s, 1H), 10.64 (s, 1H), 7.73-7.66 (m,2H), 7.58-7.48 (m, 3H).

Synthesis of 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5-oxide (89): A Common Intermediate

To a stirring solution of 6 (2.5 g, 9.21 mmol) in CH₂Cl₂ (50 mL) underinert atmosphere was added m-chloro perbenzoic acid (1.59 g, 9.21 mmol)at RT and stirred for 48 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was the volatiles wereremoved in vacuo to obtain the crude. The crude was triturated with 10%MeOH/CH₂Cl₂ (2×5 mL), isopropanol (10 mL) to afford compound 89 (2.3 g,87%) as white solid. TLC: 10% MeOH/CH₂Cl₂+0.05 mL CH₃COOH (R_(f): 0.4);¹H NMR (DMSO-d₆, 500 MHz): δ 13.36 (br s, 1H), 11.08 (s, 1H), 7.96 (d,J=7.8 Hz, 1H), 7.92-7.87 (m, 1H), 7.85-7.66 (m, 3H), 7.63 (t, J=7.8 Hz,1H), 7.53 (t, J=7.8 Hz, 1H);

Synthesis of 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (92): A Common Intermediate

Synthesis of methyl 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylate (90)

To a stirring solution of 6 (500 mg, 1.84 mmol) in MeOH:CH₂Cl₂ (1:1, 20mL) under argon atmosphere was added CH₂N₂ (insitu prepared usingN-nitrosomethyl urea (0.95 g, 9.2 mmol)+KOH (0.51 g, 9.22 mmol) at 0°C.; warmed to RT and stirred for 1 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 20% EtOAc/hexanes to afford compound 90 (450 mg,86%) as white solid. TLC: 30% EtOAc/hexanes (R_(f): 0.5); ¹H-NMR(DMSO-d₆, 500 MHz): δ 10.82 (s, 1H), 7.82 (s, 1H), 7.75-7.69 (m, 3H),7.58-7.63 (m, 3H), 3.82 (s, 3H).

Synthesis of methyl 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylate 5, 5-dioxide (91)

To a stirring solution of 90 (5 g, 17.54 mmol) in acetic acid (25 mL)was added 30% aqueous hydrogen peroxide (100 mL) at 0° C.; warmed to 50°C. and stirred for 72 h. The reaction was monitored by TLC; aftercompletion of the reaction, the obtained solid was filtered, washed withwater (100 mL), 10% EtOAc/hexanes (100 mL) and dried in vacuo to affordcompound 91 (3.5 g, 64%) as white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f):0.3); ¹H NMR (DMSO-d₆, 500 MHz): δ 11.58 (s, 1H), 8.09 (d, J=8.4 Hz,1H), 8.01-7.95 (m, 3H), 7.93-7.83 (m, 3H), 3.88 (s, 3H);

Synthesis of 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (92)

To a stirring solution of compound 91 (3.5 g, 11.04 mmol) in a mixtureof THF:MeOH:H₂O (2:2:1, 25 mL) was added lithium hydroxide monohydrate(1.3 g, 33.12 mmol) portion wise for 10 min at 0° C.; warmed to RT andstirred for 3 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with water (20 mL) and acidified with 1 N HCl to pH˜2. Theobtained solid was filtered, washed with isopropyl alcohol (15 mL) anddried in vacuo to obtain compound 92 (2.8 g, 84%) as white solid. TLC:5% MeOH/CH₂Cl₂ (R_(f): 0.1); 41 NMR (DMSO-d₆, 400 MHz): δ 13.65 (br s,1H), 11.55 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 8.03-7.82 (m, 6H).

Synthesis of 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8carboxylic acid 5, 5-dioxide (95): A Common Intermediate

Synthesis of methyl 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylate (93)

To a stirring solution of 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f][1, 4] thiazepine-8-carboxylic acid 20 (400 mg, 1.40 mmol) in MeOH (30mL) under argon atmosphere was added CH₂N₂ [insitu prepared usingN-nitrosomethyl urea (723 mg, 7.01 mmol)+30% KOH solution (100 mL) indiethyl ether (200 mL)] at 0° C. and stirred for 3 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo to obtain the crude, which was triturated with diethylether (2×20 mL) and dried in vacuo to afford compound 93 (300 mg, 71%)as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.8); ¹H-NMR(DMSO-d₆, 500 MHz): δ 10.40 (s, 1H), 7.83-7.79 (m, 1H), 7.72-7.65 (m,2H), 7.64-7.56 (m, 3H), 3.95 (s, 3H), 2.58 (s, 3H); LC-MS: 95.08%; 299.8(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.38 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of methyl 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylate 5, 5-dioxide (94)

To a stirring solution of 93 (300 mg, 1.00 mmol) in acetic acid (4 mL)was added 30% hydrogen peroxide (8 mL) at 0° C.; warmed to 60° C. andstirred for 72 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with ice-cold water (50mL), stirred for 15 min, the obtained solid was filtered, washed withwater (100 mL) and dried in vacuo to afford compound 94 (210 mg, 63%) asan off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H NMR (DMSO-d₆,500 MHz): δ 10.86 (s, 1H), 7.94-7.89 (m, 3H), 7.88-7.76 (m, 2H), 7.67(d, J=8.4 Hz, 1H), 3.83 (s, 3H), 2.43 (s, 3H). LC-MS: 94.24%; 331.9(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.22 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (95)

To a stirring solution of compound 94 (230 mg, 0.69 mmol) inTHF:MeOH:H₂O (2:2:1, 20 mL) was added lithium hydroxide monohydrate (87mg, 2.08 mmol) portion wise for 10 min at 0° C.; warmed to RT andstirred for 24 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with water (20 mL) and acidified with 3 N HCl to pH˜3. Theobtained solid was filtered, washed with water (20 mL) and dried invacuo to obtain compound 95 (210 mg, 95%) as an off-white solid. TLC:10% MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H NMR (DMSO-d₆, 400 MHz): δ 13.62 (br s,1H), 10.85 (s, 1H), 7.97-7.84 (m, 4H), 7.82-7.79 (m, 1H), 7.65 (d, J=8.4Hz, 1H), 2.43 (s, 3H). LC-MS: 96.06%; 317.9 (M⁺+1); (column; X SelectCSH C-18, (50×3.0 mm, 2.5 μm); RT 1.68 min. 2.5 mM Aq. NH4OOCH+5% ACN:ACN+5% 2.5 mM Aq.NH4OOCH, 0.8 mL/min).

Synthesis 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (104): A Common Intermediate

Synthesis of 1-bromo-4-fluoro-2-methyl-3-nitrobenzene (97)

To 1-fluoro-3-methyl-2-nitrobenzene 96 (5 g, 32.25 mmol) at 0° C. underargon atmosphere was added concentrated sulfuric acid:trifluoroaceticacid (1:2, 45 mL). To this was added N-bromosuccinimide (8.61 g, 48.37mmol) portion wise for 15 min; warmed to RT and stirred for 5 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was poured into ice-cold water (200 mL), theprecipitated solid was filtered, washed with water (100 mL) and dried invacuo to afford the crude. The crude was purified through silica gelflash column chromatography using 1-2% EtOAc/hexanes to afford compound97 (5.1 g, 68%). TLC: 5% EtOAc/hexanes (R_(f): 0.8); TLC: 30%EtOAc/hexanes (R_(f): 0.3). ¹H NMR (DMSO-d₆, 400 MHz): δ 7.96 (dd,J=8.9, 5.2 Hz, 1H), 7.47 (t, J=9.2 Hz, 1H), 22.35 (m, 3H);

Synthesis of methyl 2-((4-bromo-3-methyl-2-nitrophenyl) thio) benzoate(98)

To a stirring solution of compound 97 (5.1 g, 21.79 mmol) in DMF (80 mL)under argon atmosphere were added cesium carbonate (10.62 g, 32.67mmol), methyl 2-mercaptobenzoate 1 (4.03 g, 23.97 mmol) at RT andstirred for 2 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with ice-cold water (100mL), the precipitated solid was filtered, washed with hexane (100 mL)and diethyl ether (100 mL) and dried in vacuo to afford compound 98 (7.0g, 84%) as an off-white solid. TLC: 10% EtOAc/hexanes (R_(f): 0.3); ¹HNMR (DMSO-d₆, 400 MHz): δ 8.09-7.85 (m, 2H), 7.55-7.46 (m, 2H), 7.34(td, J=7.6, 1.1 Hz, 1H), 6.81 (dd, J=8.2, 0.8 Hz, 1H), 3.87 (s, 3H),2.35 (s, 3H); LC-MS: 98.98%; 383.2 (M+2)⁺; (Column; X-select CSH C-18(50×3.0 mm, 2.5 μm); RT 4.99 min. 2.5 mM Aq. NH₄OAc:ACN, 0.8 mL/min).

Synthesis of methyl 2-((2-amino-4-bromo-3-methylphenyl) thio) benzoate(99)

To a stirring solution of compound 98 (7 g, 18.32 mmol) in acetic acid(100 mL) was added iron powder (10.2 g, 182.7 mmol) at RT; heated to 80°C. and stirred for 16 h. The reaction was monitored by TLC and LC-MS;after completion of the reaction, the reaction mixture was filteredthrough celite, the filtrate was concentrated in vacuo. The residue wasdiluted with EtOAc (200 mL), washed with water (2×100 mL). The organicextract was dried over sodium sulfate, filtered and concentrated invacuo to compound 99 (5.8 g, 90%) as an off-white solid. TLC: 10%EtOAc/hexanes (R_(f): 0.2); LC-MS: 98.31%; 353.9 (M⁺+2); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 3.06 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 2-((2-amino-4-bromo-3-methylphenyl) thio) benzoic acid(100)

To a stirring solution of compound 99 (4.8 g, 13.63 mmol) in THF:H₂O(3:1, 120 mL) was added lithium hydroxide monohydrate (1.72 g, 40.95mmol) at RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The residue was diluted with water (20 mL) and acidified with 2 N HCl topH˜4-5. The obtained solid was filtered, washed with (50 mL) and driedin vacuo to obtain compound 100 (4 g, 87%) as an off-white solid. TLC:20% EtOAc/hexanes (R_(f): 0.2); LC-MS: 98.82%; 339.9 (M⁺+2); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.67 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 8-bromo-9-methyldibenzo [b, f] [1, 4] thiazepin-11(10H)-one(101)

To a stirring solution of compound 100 (4.7 g, 13.90 mmol) in THF (100mL) under inert atmosphere was added CDI (13.50 g, 83.32 mmol) at RT andstirred for 24 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The pH of the residuewas adjusted to ˜2 using 2 N HCl. The precipitated solid was filtered,washed with water (50 mL) and dried in vacuo to afford compound 101 (3g, 68%) as white solid. TLC: 30% EtOAc/hexanes (R_(f): 0.4) ¹H NMR(DMSO-d₆, 400 MHz): δ 10.36 (s, 1H), 7.68-7.63 (m, 1H), 7.54-7.49 (m,1H), 7.49-7.36 (m, 4H), 2.41 (s, 3H);

Synthesis of methyl 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylate (93)

To a stirring solution of compound 101 (1.5 g, 4.68 mmol) in MeOH (30mL) in a steel bomb under inert atmosphere were added dppf (259 mg, 0.46mmol), sodium acetate (1.15 g, 14.02 mmol), Pd(OAc)₂ (105 mg, 0.46 mmol)at RT and heated to 100° C. under CO gas atmosphere (150 psi) andstirred for 24 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was filtered through celite. Thefiltrate was concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column flash chromatography using 10-20%EtOAc/hexanes to afford compound 93 (1.1 g, 79%). TLC: 20% EtOAc/hexanes(R_(f): 0.2); LC-MS: 98.18%; 299.9 (M+1)⁺; (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 2.38 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min).

Synthesis of methyl 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylate 5, 5-dioxide (94)

To a compound 93 (1.1 g, 3.67 mmol) in 1, 2 dichloro ethane:CH₃CN:H₂O(1:1:2, 40 mL) were added sodium metaperiodate (2.35 g, 11.03 mmol),ruthenium chloride (38 mg, 0.18 mmol) at RT and stirred for 16 h. Thereaction was monitored by TLC; after completion, the reaction mixturewas diluted with ice-cold water (50 mL) and extracted with EtOAc (2×75mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to afford compound 94 (1 g, 83%) asan white solid. TLC: 40% EtOAc/hexanes (R_(f). 0.2); ¹H NMR (DMSO-d₆,400 MHz): δ 10.87 (s, 1H), 7.95-7.84 (m, 4H), 7.83-7.78 (m, 1H), 7.68(d, J=8.3 Hz, 1H), 3.85 (s, 3H), 2.45 (s, 3H); LC-MS: 98.10%; 332.0(M+1)⁺; (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.16 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (95)

To a stirring solution of compound 94 (1.07 g, 3.23 mmol) in THF:H₂O(3:1, 18 mL) was added lithium hydroxide monohydrate (407 mg, 9.69 mmol)at 0° C.; warmed to RT and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo. The pH of the residue was acidified with 2 N HCl to ˜2. Theprecipitated solid was filtered, washed with water (50 mL), hexane (20mL) and dried in vacuo to afford 95 (950 mg, 93%) as white solid. TLC:5% MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H NMR (DMSO-d₆, 400 MHz): δ 3.63 (br s,1H), 10.85 (s, 1H), 7.96-7.84 (m, 4H), 7.83-7.78 (m, 1H), 7.67 (d, J=8.1Hz, 1H), 2.48 (s, 3H); LC-MS: 98.67%; 317.9 (M+1)⁺; (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.81 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 7-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (105): A Common Intermediate

Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl)sulfonyl)-2-methyl-5-nitrobenzoate (102)

To a stirring solution of methyl 5-amino-4-((2-(methoxycarbonyl) phenyl)thio)-2-methylbenzoate 16 & 17 (4 g, 12.08 mmol) in acetic acid (25 mL)was added 30% H₂O₂ (20 mL) at 0° C.; heated to 70° C. and stirred for 16h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was diluted with water (20 mL) and the pH wasadjusted to ˜7 using 10% Na₂CO₃ solution (50 mL) and extracted withEtOAc (150 mL). The organic extract was dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified by column chromatography using 30% EtOAc/hexanes to affordcompound 102 (1.2 g) as yellow syrup. TLC: 40% EtOAc/hexanes (R_(f):0.4); LC-MS: 34.05%; 392.1 (M−1)⁺; (column; X-select C18, (50×3.0 mm,2.5 μm); RT 4.26 min. 2.5 mM Aq. NH₄OAc:ACN: 0.8 mL/min).

Synthesis of methyl 5-amino-4-((2-(methoxycarbonyl) phenyl)sulfonyl)-2-methylbenzoate (103)

To a stirring solution of compound 102 (500 mg, 1.27 mmol) in MeOH (25mL) under inert atmosphere was added 10% Pd/C (200 mg, 50% wet) at RTunder hydrogen atmosphere (balloon pressure) and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite, washed with MeOH (50 mL).The filtrate was removed in vacuo to obtain the crude compound 103 (300mg, 60%, over 2 steps) as yellow syrup. TLC: 40% EtOAc/hexanes (R_(f):0.4); LC-MS: 98.20%; 364.1 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 2.45 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.11 (dd, J=7.8, 1.1Hz, 1H), 7.84-7.70 (m, 2H), 7.65 (dd, J=7.5, 1.3 Hz, 1H), 7.52 (s, 1H),7.28 (s, 1H), 6.14 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 2.35 (s, 3H);

Synthesis of 5-amino-4-((2-carboxyphenyl) sulfonyl)-2-methylbenzoic acid(104)

To a stirring solution of compound 103 (1.2 g, 3.26 mmol) in THF:H₂O(3:1, 20 mL) was added lithium hydroxide monohydrate (692 mg, 16.48mmol) at RT; heated to reflux and stirred for 32 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The pH of the residue was acidified with 2 N HCl to˜2. The precipitated solid was filtered and dried in vacuo to affordcompound 104 (600 mg, 59%) as an off-white solid. The crude was carriedfor next step without further purification. TLC: 30% EtOAc/hexanes(R_(f): 0.3); LC-MS: 81.82%; 335.9 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 1.78 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min). ¹H NMR (DMSO-d₆, 400 MHz): δ 13.12 (br s,1H), 8.05-7.97 (m, 1H), 7.74 (td, J=7.5, 1.1 Hz, 1H), 7.66 (td, J=7.7,1.4 Hz, 1H), 7.60 (dd, J=7.5, 1.1 Hz, 1H), 7.56 (s, 1H), 7.23 (s, 1H),6.13 (br s, 2H), 2.33 (s, 3H);

Synthesis of 7-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (105)

To a stirring solution of compound 104 (650 mg, 1.94 mmol) in THF (15mL) under inert atmosphere was added CDI (1.59 g, 9.70 mmol) at 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was acidifiedwith 6 N HCl to pH˜2. The obtained solid was filtered and further driedand dried in vacuo to afford compound 105 (350 mg, 59%) as an off-whitesolid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); LC-MS: 71.53%; 317.9 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.45 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 7-ethyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (117): A Common Intermediate

Synthesis of methyl 2-bromo-4-fluorobenzoate (62)

To a stirring solution of 2-bromo-4-fluorobenzoic acid 106 (20 g, 91.32mmol) in MeOH (200 mL) under inert atmosphere was added concentratedsulfuric acid (100 mL) dropwise for 20 min at 0° C.; heated to refluxand stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. Theresidue was diluted with ice-cold water (100 mL) and extracted withEtOAc (300 mL). The organic extract was washed with saturated NaHCO₃solution (2×100 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to afford compound 62 (16.5 g, 78%) as pale yellowoil. TLC: 10% EtOAc/hexanes (R_(f): 0.8). ¹H-NMR (DMSO-d₆, 500 MHz): δ7.88 (dd, J=8.8, 6.2 Hz, 1H), 7.75 (dd, J=8.7, 2.6 Hz, 1H), 7.39 (td,J=8.5, 2.6 Hz, 1H), 3.85 (s, 3H).

Synthesis of methyl 2-ethyl-4-fluorobenzoate (107)

To a stirring solution of zinc(II) bromide (19.3 g, 85.77 mmol) in THF(200 mL) under argon atmosphere was added ethyl magnesium bromide (28.6mL, 85.83 mmol, 3 M solution in Et₂O) dropwise for 10 min. The reactionmixture was cooled to −78° C., added Pd(ddpf)Cl₂ (3.13 g, 4.27 mmol) andcompound 62 (10 g, 42.91 mmol), warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was cooled to 0° C., quenched with saturated ammoniumchloride solution (100 mL) and extracted with EtOAc (2×150 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel flash column chromatography using 2-4% EtOAc/hexanesto afford compound 107 (6.5 g, 83%) as pale yellow liquid. TLC: 10%EtOAc/hexanes (R_(f): 0.8). ¹H-NMR (DMSO-d₆, 400 MHz): δ 7.86 (dd,J=8.8, 6.1 Hz, 1H), 7.22 (dd, J=10.2, 2.7 Hz, 1H), 7.14 (td, J=8.5, 2.7Hz, 1H), 3.82 (s, 3H), 2.92 (q, J=7.4 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H).

Synthesis of methyl 2-ethyl-4-fluoro-5-nitrobenzoate (108)

To a stirring solution of compound 107 (6.5 g, 35.71 mmol) inconcentrated sulphuric acid (100 mL) under inert atmosphere at 0° C. wasadded fuming nitric acid (1.5 mL, 35.70 mmol) dropwise for 5 min, warmedto RT and stirred for 2 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withice-cold water (300 mL), extracted with EtOAc (2×200 mL), washed withsaturated NaHCO₃ solution (2×50 mL) and brine (50 mL). The organicextract was dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified by combiflashchromatography using 5% EtOAc/hexanes to afford compound 108 (1.8 g,22%) as colorless liquid. TLC: 5% EtOAc/hexanes (R_(f): 0.4). ¹H-NMR(DMSO-d₆, 500 MHz): δ 8.52 (d, J=8.1 Hz, 1H), 7.66 (d, J=12.8 Hz, 1H),3.89 (s, 3H), 3.01 (q, J=7.5 Hz, 2H), 1.20 (t, J=7.5 Hz, 3H).

Synthesis of methyl 2-ethyl-4-((2-(methoxycarbonyl) phenyl)thio)-5-nitrobenzoate (109)

To a stirring solution of compound 108 (1.8 g, 7.92 mmol) in DMF (30 mL)under argon atmosphere were added methyl 2-hydroxybenzoate 1 (1.46 g,8.72 mmol), cesium carbonate (3.90 g, 11.90 mmol) at 0° C.; warmed to RTand stirred for 4 h. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was diluted with water (100 mL)and extracted with EtOAc (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified by combiflash chromatography using2-10% EtOAc/hexanes to afford compound 109 (2.4 g, 81%) as yellow solid.TLC: 20% EtOAc/hexanes (R_(f): 0.4). ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.59(s, 1H), 7.97-7.92 (m, 1H), 7.75-7.65 (m, 3H), 6.84 (s, 1H), 3.87 (s,3H), 3.70 (s, 3H), 2.79 (q, J=7.5 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H).

Synthesis of methyl 5-amino-2-ethyl-4-((2-(methoxycarbonyl) phenyl)thio) benzoate (110)

A stirring solution of compound 109 (2.4 g, 6.40 mmol) in MeOH (50 mL)was evacuated for 5 min and under inert atmosphere was added 10% Pd/C(1.2 g, 50% wet) at RT and stirred under hydrogen atmosphere (balloonpressure) at RT for 24 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was filtered throughcelite and washed with MeOH (100 mL). The crude was purified bycombiflash chromatography using 5-20% EtOAc/hexanes to afford compound110 (1.4 g, 63%) as white solid. TLC: 10% EtOAc/hexanes (R_(f): 0.2); ¹HNMR (DMSO-d₆, 400 MHz): δ 7.95 (dd, J=7.9, 1.4 Hz, 1H), 7.44-7.37 (m,1H), 7.27-7.20 (m, 3H), 6.67 (dd, J=8.2, 0.9 Hz, 1H), 5.42 (s, 2H), 3.88(s, 3H), 3.83 (s, 3H), 2.71 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.4 Hz, 3H);LC-MS: 97.16%; 345.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 2.88 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 5-amino-4-((2-carboxyphenyl) thio)-2-ethylbenzoic acid(111)

To a stirring solution of compound 110 (1.4 g, 4.05 mmol) in THF:H₂O(3:1, 40 mL) was added lithium hydroxide monohydrate (852 mg, 20.28mmol) portion wise for 10 min at RT, heated to reflux and stirred for 24h. The reaction was monitored by TLC and LC-MS; after completion of thereaction, the volatiles were removed in vacuo and the pH of the aqueouslayer was acidified with 2 N HCl to ˜3. The precipitated solid wasfiltered washed with water (50 mL), n-hexane (30 mL) dried in vacuo toafford compound 111 (1.0 g 78%) as an off-white solid. TLC: 20%EtOAc/hexanes (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 13.38-12.60 (m,2H), 7.94 (dd, J=7.8, 1.4 Hz, 1H), 7.40-7.34 (m, 1H), 7.24 (d, J=11.2Hz, 2H), 7.19 (td, J=7.5, 1.1 Hz, 1H), 6.65 (dd, J=8.2, 0.8 Hz, 1H),5.33 (br s, 2H), 2.74 (q, J=7.5 Hz, 2H), 1.09 (t, J=7.4 Hz, 3H); LC-MS:99.36%; 317.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 2.09 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 7-ethyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (112)

To a stirring solution of compound 111 (1 g, 3.15 mmol) in THF (20 mL)under inert atmosphere was added CDI (1.53 g, 9.46 mmol) at RT andstirred for 24 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with water (50 mL), cooled to 0° C. and the pH was adjusted to˜2 using 2 N HCl. The precipitated solid was filtered, washed with water(50 mL), hexane (20 mL) and dried in vacuo to afford compound 112 (710mg, 75%) as white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H NMR(DMSO-d₆, 400 MHz): δ 13.12 (br s, 1H), 10.69 (s, 1H), 7.71-7.67 (m,1H), 7.61 (s, 1H), 7.56-7.42 (m, 4H), 2.85 (q, J=7.4 Hz, 2H), 1.11 (t,J=7.5 Hz, 3H).

Synthesis of 7-ethyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (113)

To a stirring solution of compound 112 (700 mg, 2.34 mmol) in 1, 2dichloro ethane:CH₃CN:H₂O (1:1:2, 40 mL) were added sodium metaperiodate(1.49 g, 6.99 mmol), ruthenium chloride (26.3 mg, 0.11 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC and LCMS; aftercompletion the volatiles were removed in vacuo. The precipitated solidwas filtered, washed with water (50 mL), hexane (20 mL) and diethylether(20 mL), dried in vacuo to afford compound 113 (650 mg, 84%) as palebrown solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400MHz): δ 11.39 (s, 1H), 8.00-7.95 (m, 2H), 7.93-7.84 (m, 2H), 7.83 (s,1H), 7.70 (s, 1H), 2.91 (q, J=7.4 Hz, 2H), 1.14 (t, J=7.5 Hz, 3H);LC-MS: 86.02%; 331.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 2.06 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 7-methoxy-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (124): A Common Intermediate

Synthesis of methyl 4-fluoro-2-methoxy-5-nitrobenzoate (115)

To a stirring solution of methyl 4-fluoro-2-methoxybenzoate 114 (10 g,27.17 mmol) in sulfuric acid (14 mL) under inert atmosphere was addedthe mixture of nitric acid (0.90 mL, 21.73 mmol) and sulfuric acid (1mL) at −5° C. and stirred for 5 min. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (25 mL) and extracted with CH₂Cl₂ (2×30 mL). The combined quenchedwith ice-cold water (100 mL) and extracted with EtOAc (2×200 mL). Thecombined organic extracts were washed with saturated NaHCO₃ solution(100 mL), dried over sodium sulfate, filtered and concentrated in vacuoto obtain the crude. The crude was purified through silica gel columnchromatography using 20% EtOAc/hexanes to afford compound 115 (5 g, 40%)as colorless syrup. TLC: 20% EtOAc/hexanes (R_(f): 0.4); ¹H-NMR (CDCl₃,400 MHz): δ 8.69 (d, J=8.8 Hz, 1H), 6.83 (d, J=12.8 Hz, 1H), 4.01 (s,3H), 3.92 (s, 3H).

Synthesis of methyl 2-methoxy-4-((2-(methoxycarbonyl) phenyl)thio)-5-nitrobenzoate (116)

To a stirring solution of compound 115 (5 g, 21.8 mmol) in DMF (50 mL)under inert atmosphere were added methyl 2-mercaptobenzoate 1 (4 g,24.01 mmol), cesium carbonate (8.5 g, 26.16 mmol) at RT; heated to 80°C. and stirred for 4 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted withice-cold water (250 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 25% EtOAc/hexanes toafford compound 116 (6 g, 79%) as an off-white solid. TLC: 30%EtOAc/hexanes (R_(f): 0.3); ¹H-NMR (CDCl₃, 400 MHz): δ 8.80 (s, 1H),7.94-7.92 (m, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.61-7.59 (m, 2H), 6.30 (s,1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.52 (s, 3H).

Synthesis of methyl 5-amino-2-methoxy-4-((2-(methoxycarbonyl) phenyl)thio) benzoate (117)

To a stirring solution of compound 116 (6 g, 0.53 mmol) in MeOH (50 mL)under inert atmosphere was added 10% Pd/C (600 mg) at RT and stirredunder hydrogen atmosphere (balloon pressure) for 20 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas filtered through celite and the filtrate was concentrated in vacuoto obtain the crude. The crude was purified through silica gel columnchromatography using 25% EtOAc/hexanes to afford compound 117 (2 g, 36%)as sticky solid. TLC: 40% EtOAc/hexanes (R_(f): 0.5); ¹H NMR (CDCl₃, 400MHz): δ 8.04 (dd, J=7.8, 1.4 Hz, 1H), 7.32-7.28 (m, 1H), 7.28-7.26 (m,1H), 7.19-7.14 (m, 1H), 7.13 (s, 1H), 6.76 (dd, J=8.2, 0.9 Hz, 1H), 4.06(s, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 3.81 (s, 3H); LC-MS: 95.75%; 347.9(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.43 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-amino-4-((2-carboxyphenyl) thio)-2-methoxybenzoic acid(118)

To a stirring solution of compound 117 (2 g, 5.76 mmol) in THF:H₂O (4:1,25 mL) was added lithium hydroxide monohydrate (1.69 g, 40.34 mmol) atRT; heated to 80° C. and stirred for 24 h. The reaction was monitored byTLC and LC-MS; after completion of the reaction, the volatiles wereremoved in vacuo. The pH of the aqueous layer was acidified with 2 N HClto ˜2. The precipitated solid was filtered, triturated with EtOAc (10mL) and dried in vacuo to afford compound 118 (1.4 g 77%) as anoff-white solid. TLC: 40% EtOAc/hexanes (R_(f): 0.1); ¹H NMR (DMSO-d₆,400 MHz): δ 13.19 (br s, 1H), 7.96 (dd, J=7.8, 1.5 Hz, 1H), 7.44-7.37(m, 2H), 7.24 (td, J=7.5, 1.0 Hz, 1H), 7.16 (s, 1H), 6.69 (dd, J=0.8,8.1 Hz, 1H), 3.72 (s, 3H); LC-MS: 96.65%; 319.9 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.81 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 7-methoxy-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (119)

To a stirring solution of compound 118 (1.3 g, 4.07 mmol) in THF (25 mL)under inert atmosphere was added CDI (1.95 g, 12.22 mmol) at 0° C.;warmed to RT and stirred for 24 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The pH of the residue was adjusted to ˜2 using 6 N HCl. The precipitatedsolid was filtered, washed with water (2×20 mL) dried in vacuo andtriturated with 50% EtOAc/hexanes (5 mL) and dried in vacuo to affordcompound 119 (1 g, 82%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.4); ¹H NMR (DMSO-d₆, 500 MHz): δ 14.41 (br s, 1H), 10.55 (s,1H), 7.71-7.67 (m, 1H), 7.56-7.44 (m, 4H), 7.28 (s, 1H), 3.81 (s, 3H);

Synthesis of 7-methoxy-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (120)

To a stirring solution of compound 119 (1 g, 3.32 mmol) in 1, 2 dichloroethane:CH₃CN:H₂O (1:1:2, 40 mL) were added sodium metaperiodate (2.17 g,9.96 mmol), ruthenium chloride (37.35 mg, 0.16 mmol) at 0° C.; warmed toRT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion the volatiles were removed in vacuo to obtain the crude. Thecrude was triturated with EtOAc (10 mL) and dried in vacuo to affordcompound 120 (700 mg, 64%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.1); TLC eluted twice; H NMR (DMSO-d₆, 500 MHz, DMSO-d₆): δ13.37 (br s, 1H), 11.25 (s, 1H), 8.01-7.95 (m, 2H), 7.90 (t, J=7.5 Hz,1H), 7.88-7.84 (m, 1H), 7.58 (s, 1H), 7.50 (s, 1H), 3.90 (s, 3H); LC-MS:95.49%; 333.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.79 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 7-chloro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (130): A Common Intermediate

Synthesis of 2-chloro-4-((2-(methoxycarbonyl) phenyl)thio)-5-nitrobenzoic acid (122)

To a stirring solution of 2-chloro-4-fluoro-5-nitrobenzoic acid 121 (5g, 22.76 mmol) in DMF (100 mL) under inert atmosphere were added methyl2-mercaptobenzoate 1 (4.2 g, 25.04 mmol), cesium carbonate (3.1 g, 9.54mmol) at RT and stirred for 12 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withice-cold water (100 mL) and washed with EtOAc (2×250 mL). The pH of theaqueous layer was adjusted to ˜2 with 2 N HCl and extracted with EtOAc(2×200 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 1-2MeOH/CH₂Cl₂ to afford compound 122 (4 g, 48%) as yellow solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.5). ¹H-NMR (DMSO-d₆, 500 MHz): δ 13.97 (br s, 1H),8.62 (s, 1H), 7.99-7.94 (m, 1H), 7.77-7.69 (m, 3H), 6.87 (s, 1H), 3.75(s, 3H); LC-MS (Agilent Ion trap): 77.39%; 366.1 (M−1)⁺; (column;X-select C-18 (50×3.0 mm, 2.5 um); RT 3.18 min. 2.5 mM Aq. NH₄OAc:ACN;0.8 mL/min).

Synthesis of 2-chloro-4-((2-(methoxycarbonyl) phenyl)sulfonyl)-5-nitrobenzoic acid (123)

To a stirring solution of compound 122 (4 g, 10.89 mmol) in 1, 2dichloro ethane:CH₃CN:H₂O (1:1:2, 40 mL) were added sodium metaperiodate(7 g, 32.72 mmol), ruthenium chloride (10 mg, 0.048 mmol) at 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion the reaction mixture was diluted with water (100 mL)and washed with EtOAc (2×100 mL). The pH of the aqueous layer wasadjusted to ˜2 with 2 N HCl and extracted with EtOAc (2×200 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to afford compound 123 (3.1 g, 72%) as anoff-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 500MHz): δ 14.53 (br s, 1H), 8.47 (s, 1H), 8.18-8.15 (m, 1H), 8.11 (s, 1H),7.99-7.85 (m, 3H), 3.76 (s, 3H); LC-MS (Agilent Ion trap): 99.64%; 397.9(M−1)⁺; (column; X-select C-18 (50×3.0 mm, 2.5 um); RT 2.97 min. 2.5 mMAq. NH₄OAc:ACN; 0.8 mL/min).

Synthesis of 5-amino-2-chloro-4-((2-(methoxycarbonyl) phenyl) sulfonyl)benzoic acid (124)

To a stirring solution of compound 123 (2.9 g, 7.26 mmol) in MeOH (30mL) was added stannous chloride (4.1 g, 21.80 mmol) at RT; heated to 60°C. and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. Theresidue was added water (100 mL) and extracted with EtOAc (2×100 mL).The organic extract was dried over sodium sulfate, filtered andconcentrated in vacuo to afford compound 124 (1.2 g, 44%) as anoff-white solid. TLC: 20% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H-NMR (DMSO-d₆, 400MHz): δ 13.66 (br s, 1H), 8.26 (td, J=7.8, 1.1 Hz, 1H), 7.83 (td, J=7.4,1.3 Hz, 1H), 7.77 (dd, J=7.9, 1.9 Hz, 1H), 7.69 (dd, J=7.5, 1.3 Hz, 1H),7.63 (s, 1H), 7.18 (s, 1H), 6.44 (s, 2H), 3.86 (s, 3H); LC-MS: 92.25%;369.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT2.09 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-amino-4-((2-carboxyphenyl) sulfonyl)-2-chlorobenzoic acid(125)

To a stirring solution of compound 124 (1 g, 2.71 mmol) in THF:H₂O (3:1,20 mL) was added lithium hydroxide monohydrate (1.1 g, 27.10 mmol)portion wise at RT and stirred for 12 h. The reaction was monitored byTLC and LC-MS; after completion of the reaction, the volatiles wereremoved in vacuo. The pH of the aqueous layer was acidified with 2 N HClto ˜2. The precipitated solid was filtered and dried in vacuo to affordcrude compound 125 (800 mg, 83%) as an off-white solid. TLC: 20%MeOH/CH₂Cl₂ (R_(f): 0.3).

Synthesis of 7-chloro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (126)

To a stirring solution of compound 125 (800 mg, 2.25 mmol) in THF (20mL) under inert atmosphere was added CDI (1.85 g, 11.26 mmol) at 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The pH of the residue was adjusted to ˜2 using 2 N HCl. The precipitatedsolid was filtered, washed with water (2×20 mL), hexanes (10 mL) anddried in vacuo to afford compound 126 (500 mg, 65%) as an off-whitesolid. TLC: 20% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ14.08 (br s, 1H), 11.56 (s, 1H), 8.01-7.96 (m, 3H), 7.96-7.85 (m, 2H),7.74 (s, 1H); LC-MS (Agilent Ion trap): 86.33%; 336.0 (M−1)⁺; (column;X-select C-18 (50×3.0 mm, 2.5 um); RT 6.57 min. 2.5 mM Aq. NH₄OAc:ACN;1.0 mL/min).

Synthesis of 9-chloro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (135): A Common Intermediate

Synthesis of 1-bromo-2, 4-dichloro-3-nitrobenzene (128)

To a stirring solution of 1,3-dichloro-2-nitrobenzene 127 (5 g, 26.04mmol) in concentrated sulfuric acid (150 mL) under inert atmosphere wasadded N-bromosuccinimide (4.6 g, 26.04 mmol) portion wise at RT andheated to 60° C. and stirred for 16 h. The reaction was poured intoice-cold water (100 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 2% EtOAc/hexanes toafford compound 128 (4.9 g, 70%). TLC: 5% EtOAc/hexanes (R_(f): 0.5); ¹HNMR (DMSO-d₆, 400 MHz): δ 8.11 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.9 Hz,1H).

Synthesis of methyl 3-amino-2, 4-dichlorobenzoate (129)

To a stirring solution of compound 128 (7.5 g, 27.77 mmol) in MeOH:CH₃CN(4:1, 100 mL) under inert atmosphere in a steel bomb were addedtriethylamine (12 mL, 83.33 mmol), dppf (1.53 g, 2.76 mmol), Pd(OAc)₂(500 mg, 2.27 mmol) at RT; heated to 100° C., under CO gas atmosphere(150 psi) and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was filtered throughcelite and the filtrate was concentrated in vacuo to obtain the crude.The crude was purified through silica gel column flash chromatographyusing 15% EtOAc/hexanes to afford compound 129 (5 g, 82%). TLC: 30%EtOAc/hexanes (R_(f): 0.5); ¹H NMR (DMSO-d₆, 400 MHz): δ 7.34 (d, J=8.1Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 5.79 (s, 2H), 3.83 (s, 3H);

Synthesis of methyl 2, 4-dichloro-3-nitrobenzoate (130)

To a stirring solution of compound 129 (5 g, 22.72 mmol) in glacialacetic acid (25 mL) was added 30% H₂O₂ (25 mL) at 0° C.; warmed to RTand stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(100 mL) and EtOAc (200 mL). The organic extract was dried over sodiumsulfate, filtered and concentrated in vacuo to afford compound 130 (4.1g, 73%) as brown solid. TLC: 30% EtOAc/hexanes (R_(f): 0.3); ¹H NMR(DMSO-d₆, 400 MHz): δ 8.11 (d, J=8.5 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H),3.91 (s, 3H);

Synthesis of methyl 2-chloro-4-((2-(methoxycarbonyl) phenyl)thio)-3-nitrobenzoate (131)

To a stirring solution of compound 130 (4.1 g, 16.40 mmol) in DMF (100mL) under argon atmosphere were added methyl 2-mercaptobenzoate 1 (2.75g, 16.40 mmol), cesium carbonate (16 g, 49.23 mmol) at 0° C.; warmed toRT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(500 mL) and extracted with EtOAc (200 mL). The organic extract wasdried over sodium sulfate, filtered and concentrated in vacuo tocompound 131 (1 g, 16%) as white solid. TLC: 30% EtOAc/hexanes (R_(f):0.3). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.08 (d, J=8.3 Hz, 1H), 7.98 (dd,J=7.8, 1.5 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.58-7.52 (m, 1H), 7.43 (td,J=7.6, 1.1 Hz, 1H), 7.02 (dd, J=8.0, 0.6 Hz, 1H), 3.92 (s, 3H), 3.86 (s,3H);

Synthesis of methyl 3-amino-2-chloro-4-((2-(methoxycarbonyl) phenyl)thio) benzoate (132)

To a stirring solution of compound 131 (1 g, 2.62 mmol) in acetic acid(10 mL) was added iron powder (734 mg, 13.12 mmol) at RT; heated to 60°C. and stirred for 4 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo and theresidue was diluted with EtOAc (200 mL). The organic layer was washedwith saturated sodium bicarbonate solution (100 mL) and dried oversodium sulfate, filtered and concentrated in vacuo to afford compound132 (700 mg, 76%) as brown syrup. TLC: 40% EtOAc/hexanes (R_(f): 0.7).¹H NMR (DMSO-d₆, 500 MHz): δ 7.97 (br d, J=7.5 Hz, 1H), 7.47-7.42 (m,2H), 7.26 (br t, J=7.5 Hz, 1H), 6.97 (d, J=8.1 Hz, 1H), 6.65 (br d,J=8.1 Hz, 1H), 5.76-5.73 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H); LC-MS:90.61%; 351.8 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 2.82 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 3-amino-4-((2-carboxyphenyl) thio)-2-chlorobenzoic acid(133)

To a stirring solution of compound 132 (700 mg, 1.99 mmol) in THF:H₂O(1:1, 20 mL) was added lithium hydroxide monohydrate (837 mg, 19.94mmol) portion wise for 10 min at RT and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the volatileswere removed in vacuo. The pH of the residue was adjusted to ˜2 with 1 NHCl and extracted with EtOAc (2×50 mL) The organic layer was dried oversodium sulfate, filtered and concentrated in vacuo to compound 133 (500mg, 78%) as a white solid. TLC: 40% EtOAc/hexanes (R_(f): 0.2).

¹H NMR (DMSO-d₆, 400 MHz): δ 13.29 (br s, 2H), 7.97 (dd, J=7.8, 1.4 Hz,1H), 7.44-7.38 (m, 2H), 7.26-7.21 (m, 1H), 6.95 (d, J=7.9 Hz, 1H), 6.63(d, J=7.6 Hz, 1H), 5.62 (br s, 2H); LC-MS: 94.65%; 323.9 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.98 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 9-chloro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid (134)

To a stirring solution of compound 133 (500 mg, 1.42 mmol) in THF (10mL) under inert atmosphere was added CDI (2.30 g, 14.20 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The pH of the residuewas adjusted to using 1 N HCl. The precipitated solid was filtered,washed with hexane (20 mL) and dried in vacuo to afford compound 134(300 mg, 69%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4);¹H NMR (DMSO-d₆, 400 MHz): δ 13.62 (br s, 1H), 10.41 (s, 1H), 7.72-7.63(m, 2H), 7.58-7.54 (m, 1H), 7.53-7.46 (m, 3H); LC-MS: 93.51%; 305.9(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.02 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 9-chloro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (135)

To a stirring solution of compound 134 (290 mg, 0.95 mmol) in 1, 2dichloro ethane:CH₃CN:H₂O (1:1:2, 20 mL) were added sodium metaperiodate(622 mg, 2.85 mmol), ruthenium chloride (10.70 mg, 0.047 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completion,the volatiles were removed in vacuo and the residue was extracted withEtOAc (2×75 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 10%MeOH/CH₂Cl₂ to afford compound 135 (230 mg, 72%) as brown solid. TLC:40% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ 14.08 (br s,1H), 11.13 (s, 1H), 8.01 (d, J=8.2 Hz, 1H), 7.98-7.89 (m, 3H), 7.85 (dd,J=7.5, 1.4 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H); LC-MS: 99.61%; 335.9 (M−1)⁺;(column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 1.15 min. 2.5 mM Aq.NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 11-oxo-7-(trifluoromethyl)-10, 11-dihydrodibenzo [b, f] [1,4] thiazepine-8-carboxylic acid 5, 5-dioxide (143): A CommonIntermediate

Synthesis of methyl 4-fluoro-2-(trifluoromethyl) benzoate (137)

To a stirring solution of 4-fluoro-2-(trifluoromethyl) benzoic acid 136(20 g, 96.10 mmol) in MeOH (200 mL) under inert atmosphere was addedconcentrated sulfuric acid (18.85 mL, 192.20 mmol) dropwise for 15 minat 0° C.; heated to reflux and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The residue was diluted with ice-cold water (300 mL)and extracted with diethyl ether (2×300 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to afford mixture of compound 137 (10.8 g, 51%) as colorlesssyrup. TLC: 10% EtOAc/hexanes (R_(f): 0.8). ¹H NMR (400 MHz, DMSO-d₆): δ7.96 (dd, J=8.7, 5.5 Hz, 1H), 7.81 (dd, J=9.3, 2.6 Hz, 1H), 7.68 (td,J=8.4, 2.5 Hz, 1H), 3.87 (s, 3H);

Synthesis of methyl 4-fluoro-5-nitro-2-(trifluoromethyl) benzoate (138)

To a stirring solution of compound 137 (10.8 g, 48.64 mmol) inconcentrated sulphuric acid (30 mL) under inert atmosphere at 0° C. wasadded fuming nitric acid (15 mL) dropwise for 30 min at 0° C.; heated to65° C. and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was cooled to 0° C. andslowly quenched with ice-cold water (300 mL) and extracted with EtOAc(2×300 mL). The combined organic extracts were washed with saturatedNaHCO₃ solution (300 mL) and brine (300 mL), dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column flash chromatography using 5%EtOAc/hexanes to afford compound 138 (3.5 g, 27%) as colorless syrup.TLC: 10% EtOAc/hexanes (R_(f): 0.7). ¹H NMR (400 MHz, DMSO-d₆): δ 8.63(d, J=7.3 Hz, 1H), 8.30 (d, J=11.3 Hz, 1H), 3.92 (s, 3H);

Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl)thio)-5-nitro-2-(trifluoromethyl) benzoate (139)

To a stirring solution of methyl 4-fluoro-5-nitro-2-(trifluoromethyl)benzoate 138 (4.00 g, 14.98 mmol) in DMF (80 mL) under inert atmospherewere added methyl 2-mercaptobenzoate 1 (2.52 g, 14.98 mmol) and cesiumcarbonate (7.32 g, 22.47 mmol) at 0° C.; warmed to RT and stirred for 2h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was diluted with water (200 mL) and extracted withEtOAc (2×200 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 5-7%EtOAc/hexanes to afford compound 139 (5 g, 81%) as yellow syrup. TLC:20% EtOAc/hexanes (R_(f): 0.5); ¹H NMR (DMSO-d₆, 400 MHz): δ 8.68 (s,1H), 8.03-7.96 (m, 1H), 7.77-7.70 (m, 3H), 7.25 (s, 1H), 3.90 (s, 3H),3.74 (s, 3H);

Synthesis of methyl 5-amino-4-((2-(methoxycarbonyl) phenyl)thio)-2-(trifluoromethyl) benzoate (140)

To a stirring solution of compound 139 (5 g, 12.04 mmol) in MeOH (100mL) under inert atmosphere was added 10% Pd/C (2 g) at RT and stirredunder hydrogen atmosphere (balloon pressure) at RT for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite and eluted with 50%MeOH/CH₂Cl₂ (2×150 mL). The filtrate was concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 20-25% EtOAc/hexanes to afford compound 140 (3.5 g,75%) as an off-white solid. TLC: 40% EtOAc/hexanes (R_(f): 0.5); ¹H NMR(400 MHz, DMSO-d₆): δ 7.96 (dd, J=7.8, 1.4 Hz, 1H), 7.67 (s, 1H),7.46-7.41 (m, 1H), 7.27-7.23 (m, 1H), 7.15 (s, 1H), 6.65 (dd, J=8.1, 0.7Hz, 1H), 6.40 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H);

Synthesis of 5-amino-4-((2-carboxyphenyl) thio)-2-(trifluoromethyl)benzoic acid (141)

To a stirring solution of compound 140 (3.5 g, 9.09 mmol) in THF:H₂O(3:1, 40 mL) was added lithium hydroxide monohydrate (1.90 g, 45.45mmol) at 0° C.; warmed to RT and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The residue was diluted with water (30 mL) and washedwith diethylether (2×30 mL). The aqueous layer was acidified with 6 NHCl to pH˜4. The precipitated solid was filtered and dried in vacuo toafford compound 141 (2.8 g, 86%) as an off-white solid. TLC: 40%EtOAc/hexanes (R_(f): 0.2); ¹H NMR (400 MHz, DMSO-d₆): δ 13.32 (br s,2H), 7.97 (dd, J=7.8, 1.4 Hz, 1H), 7.64 (s, 1H), 7.45-7.38 (m, 1H),7.27-7.20 (m, 1H), 7.15 (s, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.25 (br s,2H);

Synthesis of 11-oxo-7-(trifluoromethyl)-10, 11-dihydrodibenzo [b, f] [1,4] thiazepine-8-carboxylic acid (142)

To a stirring solution of compound 141 (2.6 g, 7.28 mmol) in THF (50 mL)under inert atmosphere was added CDI (5.90 g, 36.41 mmol) at 0° C.;heated to 60° C. and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The residue was poured into ice-cold water (100 mL) and the pHwas adjusted to ˜2 using 6 N HCl. The precipitated solid was filteredand dried in vacuo to afford compound 142 (710 mg, 75%) as white solid.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.3); 41 NMR (400 MHz, DMSO-d₆): δ 13.82 (brs, 1H), 11.04 (s, 1H), 7.96 (s, 1H), 7.75-7.69 (m, 1H), 7.64-7.45 (m,4H);

Synthesis of 11-oxo-7-(trifluoromethyl)-10, 11-dihydrodibenzo [b, f] [1,4] thiazepine-8-carboxylic acid 5, 5-dioxide (143)

To a stirring solution of compound 142 (1.9 g, 5.60 mmol) in 1, 2dichloro ethane:CH₃CN:H₂O (1:1:2, 100 mL) were added sodiummetaperiodate (3.6 g, 16.81 mmol), ruthenium chloride (58 mg, 0.28 mmol)at 0° C.; warmed to RT and stirred for 16 h. The reaction was monitoredby TLC; after completion, the volatiles were removed in vacuo. The solidobtained was filtered, washed with water (2×20 mL). The solid wasdissolved in 20% MeOH/CH₂Cl₂ (100 mL) and filtered through celite. Thefiltrate was concentrated in vacuo to obtain the crude, which wastriturated with n-hexane (20 mL) and dried in vacuo to afford compound143 (1.6 g, 77%) as an off-white solid. TLC: 15% MeOH/CH₂Cl₂ (R_(f):0.2); ¹H NMR (400 MHz, DMSO-d₆): δ 11.85 (s, 1H), 8.19 (s, 1H),8.05-7.99 (m, 2H), 7.97-7.87 (m, 2H), 7.78 (s, 2H); LC-MS: 98.87%; 289.9(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.08 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-fluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (144): A Common Intermediate

Synthesis of 4-fluoro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide (144)

To a stirring solution of 4-fluoro-11-oxo-10, 11-dihydrodibenzo [b, f][1, 4] thiazepine-8-carboxylic acid 76 (300 mg, 1.03 mmol) in 1, 2dichloro ethane:CH₃CN:H₂O (1:1:2, 12 mL) were added sodium metaperiodate(663 mg, 3.11 mmol), ruthenium chloride (10.7 mg, 0.05 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completionthe volatiles were removed in vacuo. The residue was diluted with water(50 mL) and extracted with EtOAc (3×50 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to afford compound 144 (220 mg, 67%) as an off-white solid. TLC:10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 13.91-13.44(m, 1H), 11.60 (s, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.94-7.84 (m, 3H),7.77-7.64 (m, 2H); LC-MS: 97.70%; 320.0 (M−1)⁺; (column; Kinetex EVOC-18 (50×3.0 mm, 2.6 um); RT 1.27 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5%2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxylic acid (149): A Common Intermediate

Synthesis of methyl 4-(2-(methoxycarbonyl) phenoxy)-3-nitrobenzoate(146)

To a stirring solution of methyl 4-fluoro-3-nitrobenzoate 2 (5 g, 25.12mmol) in DMF (75 mL) under argon atmosphere were added methyl2-hydroxybenzoate 145 (4.2 g, 27.63 mmol), cesium carbonate (8.98 g,27.64 mmol), at RT; heated to 100° C. and stirred for 2 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with ice-cold water (200 mL). The precipitated solidwas filtered, washed with n-hexane (100 mL) and dried in vacuo to affordcompound 146 (6.2 g, 75%) as an off-white solid. TLC: 30% EtOAc/hexanes(R_(f): 0.4); ¹H NMR (DMSO-d₆, 500 MHz): δ 8.54 (s, 1H), 8.11 (dd,J=8.8, 2.2 Hz, 1H), 8.02 (dd, J=7.7, 1.6 Hz, 1H), 7.80 (td, J=7.8, 1.7Hz, 1H), 7.52 (t, J=7.4 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 6.89 (d, J=8.7Hz, 1H), 3.88 (s, 3H), 3.64 (s, 3H).

Synthesis of methyl 3-amino-4-(2-(methoxycarbonyl) phenoxy) benzoate(147)

To a stirring solution of compound 146 (2 g, 6.04 mmol) in MeOH (50 mL)was evacuated for 5 min and added 10% Pd/C (1 g, 50% wet) under argonatmosphere at RT and stirred under hydrogen atmosphere (balloonpressure) at RT for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was filtered throughcelite and washed with 20% MeOH/CH₂Cl₂ (200 mL). The filtrate wasconcentrated in vacuo to obtain the crude. The crude was purified bycombiflash chromatography using 20% EtOAc/hexanes to afford compound 147(1.4 g, 77%) as an off-white solid. TLC: 30% EtOAc/hexanes (R_(f): 0.3);¹H NMR (DMSO-d₆, 400 MHz): δ 7.84 (dd, J=7.7, 1.6 Hz, 1H), 7.61-7.55 (m,1H), 7.44 (s, 1H), 7.27 (t, J=7.2 Hz, 1H), 7.13 (dd, J=8.3, 2.0 Hz, 1H),7.00 (d, J=8.0 Hz, 1H), 6.65 (d, J=8.3 Hz, 1H), 5.30 (br s, 2H), 3.80(s, 3H), 3.74 (s, 3H).

Synthesis of 3-amino-4-(2-carboxyphenoxy) benzoic acid (148)

To a stirring solution of compound 147 (1.4 g, 4.65 mmol) in THF:H₂O(3:1, 40 mL) was added lithium hydroxide monohydrate (976 mg, 23.23mmol) at RT; heated to reflux and stirred for 2 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The pH of the residue was acidified to ˜2 with 2 NHCl. The precipitated solid was filtered, washed with water (20 mL),n-pentane (20 mL) and dried in vacuo to afford compound 148 (700 mg,56%) as an off-white solid. TLC: 30% EtOAc/hexanes (R_(f): 0.0; ¹H NMR(DMSO-d₆, 400 MHz): δ 7.86 (dd, J=7.7, 1.6 Hz, 1H), 7.63 (s, 1H),7.62-7.57 (m, 1H), 7.37 (d, J=7.3 Hz, 1H), 7.31 (t, J=7.3 Hz, 1H), 7.06(d, J=8.0 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H).

Synthesis of 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxylic acid (149)

To a stirring solution of compound 148 (700 mg, 2.56 mmol) in THF (20mL) under argon atmosphere was added CDI (2.07 g, 12.77 mmol) at RT andstirred for 24 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The pH of the residuewas acidified to ˜2 using 2 N HCl. The precipitated solid was filtered,washed with n-pentane (50 mL) and dried in vacuo to afford compound 149(450 mg, 69%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2);¹H NMR (DMSO-d₆, 400 MHz): δ 13.03 (br s, 1H), 10.65 (s, 1H), 7.81-7.76(m, 2H), 7.70 (dd, J=8.4, 2.2 Hz, 1H), 7.67-7.61 (m, 1H), 7.43 (d, J=8.4Hz, 1H), 7.40-7.31 (m, 2H).

Synthesis of 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxylic acid (153): A Common Intermediate

Synthesis of methyl 2-(4-bromo-3-methyl-2-nitrophenoxy) benzoate (150)

To a stirring solution of compound 97 (1.5 g, 6.41 mmol) in DMF (30 mL)under inert atmosphere were added cesium carbonate (3.1 g, 9.54 mmol),methyl 2-hydroxybenzoate 145 (974 mg, 6.41 mmol) at RT; heated to 70° C.and stirred for 2 h. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was diluted with ice-cold water(100 mL) and the precipitated solid was filtered, washed with water (20mL), hexane (20 mL) and dried in vacuo to afford compound 150 (1.1 g,48%) as a pale brown solid. TLC: 5% EtOAc/hexanes (R_(f): 0.3); ¹H NMR(DMSO-d₆, 400 MHz): δ 7.94 (dd, J=7.8, 1.8 Hz, 1H), 7.75-7.69 (m, 2H),7.45 (td, J=7.6, 1.1 Hz, 1H), 7.27 (dd, J=8.2, 0.9 Hz, 1H), 6.65 (d,J=9.0 Hz, 1H), 3.71 (s, 3H), 2.35 (s, 3H); LC-MS: 97.42%; 364.0 (M−1)⁺,365.9 (M−2)⁺; (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 3.78min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 8-bromo-9-methyldibenzo [b, f] [1, 4] oxazepin-11(10H)-one(151)

To a stirring solution of compound 150 (900 mg, 2.46 mmol) in aceticacid (30 mL) under inert atmosphere was added iron powder (676 mg, 12.29mmol) at RT; heated to 90° C. and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with water (60 mL) and extracted with EtOAc (2×75 mL). Thecombined organic extracts were washed with aqueous NaHCO₃ solution (2×50mL) and brine (50 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to compound 151 (750mg, 91%) as pale brown solid. TLC: 10% EtOAc/hexanes (R_(f): 0.2);¹H-NMR (DMSO-d₆, 500 MHz): δ 10.17 (s, 1H), 7.72 (dd, J=7.7, 1.3 Hz,1H), 7.63-7.57 (m, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.38-7.30 (m, 2H), 7.20(d, J=8.7 Hz, 1H), 2.39 (s, 3H); LC-MS: 92.00%; 305.9 (M⁺+2); (column;Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 3.10 min. 2.5 mM Aq. NH₄OOCH+5%ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of methyl 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxylate (152)

To a stirring solution of compound 151 (800 mg, 2.63 mmol) in MeOH (80mL) in a steel bomb were added dppf (145.7 mg, 0.26 mmol), sodiumacetate (647 mg, 7.89 mmol), Pd(OAc)₂ (59 mg, 0.26 mmol) at RT; heatedto 120° C. under CO gas atmosphere (80 psi) and stirred for 24 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite and the filtrate wasconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column flash chromatography using 10-20%EtOAc/hexanes to afford compound 152 (500 mg, 68%). TLC: 20%EtOAc/hexanes (R_(f). 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 10.09 (s, 1H),7.73 (dd, J=7.8, 1.6 Hz, 1H), 7.63-7.54 (m, 2H), 7.40-7.29 (m, 3H), 3.81(s, 3H), 2.45 (s, 3H); LC-MS: 97.37%; 283.9 (M⁺+1); (column; Kinetex EVOC-18 (50×3.0 mm, 2.6 um); RT 2.68 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5%2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxylic acid (153)

To a stirring solution of compound 152 (550 mg, 1.94 mmol) in THF:H₂O(4:1, 24 mL) was added lithium hydroxide monohydrate (245 mg, 5.83 mmol)RT and reflux for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. Theresidue was diluted with water (20 mL) and acidified with 2 N HCl topH˜3-4. The obtained solid was filtered, washed with water (20 mL),n-hexane (20 mL), diethylether (20 mL) and dried in vacuo to obtaincompound 153 (310 mg, 60%) as pale brown solid. TLC: 30% EtOAc/hexanes(R_(f): 0.1); ¹H NMR (DMSO-d₆, 400 MHz): δ 13.03 (br s, 1H), 10.05 (s,1H), 7.73 (dd, J=7.7, 1.7 Hz, 1H), 7.63-7.53 (m, 2H), 7.39-7.26 (m, 3H),2.47 (s, 3H); LC-MS: 99.95%; 269.9 (M⁺+1); (column; Kinetex EVO C-18(50×3.0 mm, 2.6 um); RT 1.17 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5% 2.5mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 7-chloro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxylic acid (155): A Common Intermediate

Synthesis of 2-chloro-4-(2-(methoxycarbonyl phenoxy)-5-nitrobenzoic acid(154)

To a stirring solution of 2-chloro-4-fluoro-5-nitrobenzoic acid 121 (5g, 22.76 mmol) in DMF (50 mL) under argon atmosphere were added methyl2-hydroxybenzoate 145 (3.8 g, 25.04 mmol), cesium carbonate (14.8 g,45.53 mmol) at 0° C.; warmed to RT and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with water (100 mL) and washed with EtOAc (2×100mL). The pH of the aqueous layer was acidified to ˜2 with 2 N HCl andextracted with EtOAc (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel chromatographyusing 2-10% MeOH/CH₂Cl₂ to afford compound 154 (6 g, 75%) as anoff-white solid. TLC: 10% MeOH/to CH₂Cl₂ (R_(f): 0.3). ¹H-NMR (DMSO-d₆,400 MHz): δ 13.79 (br s, 1H), 8.55 (s, 1H), 8.02 (dd, J=7.8, 1.8 Hz,1H), 7.81-7.75 (m, 1H), 7.52 (td, J=7.7, 1.1 Hz, 1H), 7.45 (dd, J=8.2,0.9 Hz, 1H), 6.85 (s, 1H), 3.69 (s, 3H); LC-MS (Agilent Ion trap):94.80%; 352.7 (M⁺+1); (Column; X-select CSH C-18 (50×3 mm, 2.5 μm); RT3.02 min. 2.5% Aq. NH₄OAc:ACN; 0.8 mL/min).

Synthesis of 7-chloro-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxylic acid (155)

To a stirring solution of compound 154 (6 g, 17.09 mmol) in acetic acid(60 mL) was added iron powder (9.5 g, 170.94 mmol) at RT; heated to 100°C. and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. Theresidue was diluted with water (50 mL) and the pH was adjusted to ˜2with 6 N HCl. The precipitated solid was filtered and dried in vacuoafford compound 155 (4 g, 81%) as an off-white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 13.46 (br s, 1H),10.68 (s, 1H), 7.78 (dd, J=7.8, 1.6 Hz, 1H), 7.68-7.59 (m, 3H),7.41-7.32 (m, 2H); LC-MS (Agilent Ion trap): 93.44%; 289.9 (M⁺+1);(Column; X-select CSH C-18 (50×3 mm, 2.5 μm); RT 2.58 min. 2.5% Aq.NH₄OAc:ACN; 0.8 mL/min).

Synthesis of 11-oxo-7-(trifluoromethyl)-10, 11-dihydrodibenzo [b, f] [1,4] oxazepine-8-carboxylic acid (158): A Common Intermediate

Synthesis of methyl 4-(2-(methoxycarbonyl)phenoxy)-5-nitro-2-(trifluoromethyl) benzoate (156)

To a stirring solution of compound 138 (3 g, 11.23 mmol) in DMF (50 mL)under argon atmosphere were added methyl 2-hydroxybenzoate 145 (1.7 g,11.23 mmol), cesium carbonate (5.49 g, 16.85 mmol) at 0° C.; warmed toRT and stirred for 2 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(500 mL) and stirred for 1 h. The precipitated solid was filtered,washed with hexane (2×50 mL) and dried in vacuo to afford compound 156(3.5 g, 78%) as pale yellow solid. TLC: 30% EtOAc/hexanes (R_(f): 0.4);¹H NMR (400 MHz, DMSO-d₆): δ 8.63 (s, 1H), 8.02 (dd, J=7.8, 1.8 Hz, 1H),7.80 (td, J=7.8, 1.8 Hz, 1H), 7.58-7.48 (m, 2H), 7.10 (s, 1H), 3.90 (s,3H), 3.68 (s, 3H); LC-MS: 99.37%; 399.9 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.80 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of methyl 11-oxo-7-(trifluoromethyl)-10, 11-dihydrodibenzo [b,f] [1, 4] oxazepine-8-carboxylate (157)

To a stirring solution of compound 156 (3.3 g, 8.27 mmol) in acetic acid(50 mL) were added iron powder (4.6 g, 82.70 mmol) at RT; heated to 80°C. and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo and theresidue was diluted with EtOAc (200 mL) and filtered through celite. Thefiltrate was concentrated in vacuo to obtain the crude. The crude waspurified through silica gel flash column chromatography using 30-35%EtOAc/hexanes to afford compound 157 (1.9 g, 68%) as white solid. TLC:40% EtOAc/hexanes (R_(f): 0.4). LC-MS: 98.04%; 338.2 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.55 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 11-oxo-7-(trifluoromethyl)-10, 11-dihydrodibenzo [b, f] [1,4] oxazepine-8-carboxylic acid (158)

To a stirring solution of compound 157 (2.2 g, 6.52 mmol) in THF:H₂O(3:1, 20 mL) was added lithium hydroxide monohydrate (1.37 g, 32.64mmol) portion wise for 10 min at 0° C.; warmed to RT and stirred for 24h. The reaction was monitored by TLC; after completion of the reaction,the volatiles were removed in vacuo. The residue was diluted with water(20 mL) and acidified with 6 N HCl to pH˜4 and stirred for 2 h. Theobtained solid was filtered, and dried in vacuo to obtain compound 158(1.8 g, 86%) as white solid. TLC: 50% EtOAc/hexanes (R_(f): 0.1); ¹H NMR(DMSO-d₆, 400 MHz): δ 13.70 (br s, 1H), 10.91 (s, 1H), 7.84 (s, 1H),7.80 (dd, J=7.8, 1.6 Hz, 1H), 7.70-7.62 (m, 2H), 7.47 (dd, J=8.1, 0.8Hz, 1H), 7.37 (td, J=7.6, 1.1 Hz, 1H); LC-MS: 99.92%; 321.9 (M−1)⁺;(column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 0.94 min. 2.5 mM Aq.NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min);

Synthesis of 11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid (163): A Common Intermediate

Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl)amino)-3-nitrobenzoate (160)

To a stirring solution of methyl 2-aminobenzoate 159 (5 g, 33.07 mmol)in N-Methyl-2-pyrrolidone (13 mL) under inert atmosphere were addeddiisopropylethylamine (18 mL, 103.46 mmol), methyl4-fluoro-3-nitrobenzoate 2 (9.87 g, 49.21 mmol) at RT; heated to 120° C.in a sealed tube and stirred for 14 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith diethyl ether (100 mL) and stirred for 1 h. The obtained solid wasfiltered, washed with EtOAc (100 mL) and dried in vacuo to affordcompound 160 (2.9 g, 26%) as yellow solid. TLC: 30% EtOAc/hexanes(R_(f). 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 11.13 (s, 1H), 8.67 (s, 1H),8.11-7.94 (m, 2H), 7.70-7.62 (m, 2H), 7.58 (d, J=9.0 Hz, 1H), 7.32-7.27(m, 1H), 3.87 (s, 6H).

Synthesis of methyl 3-amino-4-((2-(methoxycarbonyl) phenyl) amino)benzoate (161)

To a stirring solution of compound 160 (5 g, 15.15 mmol) in MeOH (150mL) under inert atmosphere was added 10% Pd/C (2.5 g, 50% wet) at RT andstirred under hydrogen atmosphere (balloon pressure) at RT for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite and washed with 20%MeOH/CH₂Cl₂ (600 mL). The filtrate was concentrated in vacuo to obtainthe crude. The crude washed with diethyl ether:n-pentane (1:2, 30 mL)dried in vacuo to afford compound 161 (2.7 g, 60%) as yellow solid. TLC:30% EtOAc/hexanes (R_(f): 0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ 8.92 (s,1H), 7.91 (dd, J=8.0, 1.6 Hz, 1H), 7.46-7.45 (m, 1H), 7.43-7.36 (m, 1H),7.21 (s, 2H), 6.95 (dd, J=8.5, 0.6 Hz, 1H), 6.83-6.77 (m, 1H), 5.18 (s,2H), 3.85 (s, 3H), 3.80 (s, 3H).

Synthesis of 3-amino-4-((2-carboxyphenyl) amino) benzoic acid (162)

To a stirring solution of compound 161 (2.7 g, 9.00 mmol) in THF:H₂O(2.5:1, 210 mL) was added lithium hydroxide monohydrate (3.4 g, 81.00mmol) at RT; heated to 65° C. and stirred for 5 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The pH of the residue was acidified to ˜4 with 2 NHCl. The precipitated solid was filtered, washed with water (20 mL) anddried in vacuo to afford compound 162 (2.4 g, crude) as an off-whitesolid. TLC: 30% EtOAc/hexanes (R_(f): 0.1); ¹H NMR (DMSO-d₆, 400 MHz): δ12.65 (br s, 2H), 9.20 (br s, 1H), 7.90 (dd, J=8.0, 1.6 Hz, 1H),7.44-7.42 (m, 1H), 7.39-7.35 (m, 1H), 7.20-7.18 (m, 2H), 6.92 (dd,J=8.5, 0.7 Hz, 1H), 6.79-6.75 (m, 1H), 5.08 (br s, 2H).

Synthesis of 11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid (163)

To a stirring solution of compound 162 (2.4 g, 8.82 mmol) in THF (80 mL)under inert atmosphere was added CDI (5.8 g, 35.29 mmol) at RT andstirred for 24 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The pH of the residuewas adjusted to ˜2 using 2 N HCl. The precipitated solid was filtered,washed with n-pentane (50 mL) and dried in vacuo to afford compound 163(1.9 g, 85%) as pale green solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹HNMR (DMSO-d₆, 400 MHz): δ 12.66 (br s, 1H), 9.93 (s, 1H), 8.26 (s, 1H),7.70 (d, J=7.9 Hz, 1H), 7.58-7.50 (m, 2H), 7.36 (t, J=7.0 Hz, 1H), 7.02(dd, J=17.4, 8.2 Hz, 2H), 6.91 (t, J=7.4 Hz, 1H).

Synthesis of 5-methyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid (177): A Common Intermediate

Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl) (methyl)amino)-3-nitrobenzoate (164)

To a stirring solution of compound 160 (3 g, 9.09 mmol) in DMF (30 mL)under inert atmosphere were added cesium carbonate (5.9 g, 18.15 mmol),methyl iodide (0.84 mL, 13.59 mmol) at RT and stirred for 6 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with ice-cold water (60 mL) and extractedwith EtOAc (2×100 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using20% EtOAc/hexanes to afford compound 164 (2.73 g, 88%) as yellow solid.TLC: 30% EtOAc/hexanes (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 8.07(s, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.71 (dd, J=7.8, 1.5 Hz, 1H), 7.62 (t,J=7.3 Hz, 1H), 7.40-7.26 (m, 3H), 3.84 (s, 3H), 3.53 (s, 3H), 3.38 (s,3H).

Synthesis of methyl 5-methyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1,4] diazepine-8-carboxylate (165)

To a stirring solution of compound 164 (2.73 g, 7.93 mmol) in aceticacid (36 mL) under inert atmosphere was added iron powder (7 g, 127.2mmol) at RT; heated to 80° C. and stirred for 4 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with CH₂Cl₂ (50 mL), stirred for 2 h and filtered throughcelite and the filtrate was concentrated in vacuo to obtain the crude.The crude was dissolved in CH₂Cl₂ (200 mL), washed with saturatedaqueous NaHCO₃ solution (100 mL), brine (100 mL). The organic extractwas dried over sodium sulfate, filtered and concentrated in vacuo toafford compound 165 (2 g, 91%) as an off-white solid. TLC: 30%EtOAc/hexanes (R_(f): 0.4); ¹H NMR (DMSO-d₆, 500 MHz): δ 10.33 (s, 1H),7.68 (dd, J=8.5, 1.9 Hz, 1H), 7.65-7.61 (m, 2H), 7.50 (t, J=7.8 Hz, 1H),7.28 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.10 (t, J=7.4 Hz, 1H),3.80 (s, 3H), 3.33 (s, 3H).

Synthesis of 5-methyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid (166)

To a stirring solution of compound 165 (2 g, 7.09 mmol) in THF:H₂O (1:1,80 mL) was added lithium hydroxide monohydrate (900 mg, 21.42 mmol) atRT and stirred for 12 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. The pHof the residue was adjusted to ˜2 with 2 N HCl. The precipitated solidwas filtered and dried in vacuo to afford compound 166 (1.7 g, 89%) asan off-white solid. TLC: 40% EtOAc/hexanes (R_(f): 0.2); ¹H NMR(DMSO-d₆, 400 MHz): δ 12.82 (br s, 1H), 10.33 (s, 1H), 7.70-7.60 (m,3H), 7.51 (t, J=7.8 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.21 (d, J=7.8 Hz,1H), 7.11 (t, J=7.2 Hz, 1H), 3.32 (s, 3H).

Synthesis of 5-ethyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid (169): A Common Intermediate

Synthesis of methyl 4-(ethyl (2-(methoxycarbonyl) phenyl)amino)-3-nitrobenzoate (167)

To a stirring solution of compound 160 (2.9 g, 8.78 mmol) in DMF (40 mL)under inert atmosphere were added cesium carbonate (6 g, 18.46 mmol),ethyl iodide (1.06 mL, 12.82 mmol) at RT and stirred for 5 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with ice-cold water (60 mL), extracted withEtOAc (2×100 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude whichwas titurated with n-pentane (20 mL) to afford compound 167 (2.8 g, 89%)as pale yellow solid. TLC: 30% EtOAc/hexanes (R_(f): 0.5); ¹H NMR(DMSO-d₆, 500 MHz): δ 8.05 (dd, J=9.0, 2.0 Hz, 1H), 8.02 (s, 1H),7.62-7.57 (m, 2H), 7.45 (d, J=9.0 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.28(t, J=7.5 Hz, 1H), 3.94 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 3.44 (s, 3H),1.20 (t, J=7.1 Hz, 3H).

Synthesis of methyl 5-ethyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1,4] diazepine-8-carboxylate (168)

To a stirring solution of compound 167 (2.8 g, 7.82 mmol) in acetic acid(40 mL) under inert atmosphere was added iron powder (6.8 g, 125.1 mmol)at RT; heated to 80° C. and stirred for 4 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasdiluted with CH₂Cl₂ (50 mL), stirred for 2 h and filtered throughcelite. The filtrate was concentrated in vacuo to obtain the crude. Thecrude was diluted with CH₂Cl₂ (200 mL), washed with saturated aqueoussodium bicarbonate solution (100 mL) and brine (100 mL). The organicextract was dried over sodium sulfate, filtered and concentrated invacuo to afford compound 168 (2.2 g, 96%) as an off-white solid. TLC:30% EtOAc/hexanes (R_(f): 0.3); ¹H NMR (DMSO-d₆, 500 MHz): δ 10.35 (brs, 1H), 7.70 (dd, J=8.5, 1.9 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J=7.5 Hz,1H), 7.51 (t, J=8.1 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.1 Hz,1H), 7.12 (t, J=7.4 Hz, 1H), 3.31 (s, 5H), 1.11 (t, J=6.9 Hz, 3H).

Synthesis of 5-ethyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid (169)

To a stirring solution of compound 168 (2.1 g, 7.09 mmol) in THF:H₂O(1:1, 60 mL) was added lithium hydroxide monohydrate (890 mg, 21.26mmol) at RT and stirred for 12 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The pH of the residue was acidified to ˜2 with 2 N HCl. The precipitatedsolid was filtered, washed with water (50 mL) and dried in vacuo toafford compound 169 (1.6 g, 80%) as an off-white solid. TLC: 30%EtOAc/hexanes (R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 12.82 (br s,1H), 10.33 (s, 1H), 7.69-7.59 (m, 3H), 7.53-7.48 (m, 1H), 7.24 (dd,J=19.7, 8.2 Hz, 2H), 7.12 (t, J=7.5 Hz, 1H), 3.79 (br s, 2H), 1.12 (t,J=7.0 Hz, 3H).

Synthesis of 11-oxo-5-propyl-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid (172): A Common Intermediate

Synthesis of methyl3-amino-4-(2-(methoxycarbonyl) phenyl) (propyl)amino) benzoate (170)

To a stirring solution of methyl methyl 4-((2-(methoxycarbonyl) phenyl)amino)-3-nitrobenzoate 160 (2 g, 6.06 mmol) in DMF (50 mL) under argonatmosphere were added cesium carbonate (5.9 g, 18.18 mmol), iodo propane(1.17 mL, 12.12 mmol) at RT; heated to 80° C. and stirred for 14 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with EtOAc (100 mL) and washed with water(75 mL), brine (75 mL). The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 5-10%EtOAc/hexanes to afford compound 170 (1.2 g, 53%) as yellow solid. TLC:10% EtOAc/hexanes (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 8.07 (dd,J=8.9, 2.1 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.64-7.54 (m, 2H), 7.48 (d,J=8.9 Hz, 1H), 7.36 (dd, J=8.2, 0.8 Hz, 1H), 7.27 (td, J=7.6, 1.1 Hz,1H), 3.90-3.80 (m, 5H), 3.41 (s, 3H), 1.73-1.63 (m, 2H), 0.94 (t, J=7.3Hz, 3H).

Synthesis of methyl 11-oxo-5-propyl-10, 11-dihydro-5H-dibenzo [b, e][1,4] diazepine-8-carboxylate (171)

To a stirring solution of compound 170 (1.2 g, 3.22 mmol) in AcOH (12mL) under argon atmosphere was added Iron powder (2.8 g, 51.6 mmol) atRT and heated to 80° C. and stirred for 4 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasdiluted with CH₂Cl₂ filtered through celite and washed with CH₂Cl₂ (100mL). The filtrate was concentrated in vacuo. The residue was dissolvedin CH₂Cl₂ washed with saturated sodium bicarbonate solution (50 mL),brine solution (50 mL). The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude wastriturated with diethyl ether:pentane (1:1, 50 mL) filtered finallywashed with pentane (30 mL) to afford compound 171 (700 mg, 70%) as offwhite solid. TLC: 20% EtOAc/hexanes (R_(f). 0.3); ¹H NMR (DMSO-d₆, 400MHz): δ 10.34 (s, 1H), 7.71-7.65 (m, 2H), 7.61 (dd, J=7.8, 1.6 Hz, 1H),7.53-7.46 (m, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H),7.15-7.09 (m, 1H), 3.81 (s, 3H), 3.75-3.65 (br s, 2H), 1.54-1.55 (m,2H), 0.87 (t, J=7.3 Hz, 3H); LC-MS: 93.58%; 310.9 (M⁺+1); (column;Ascentis Express C-18 (50×3.0 mm, 2.7 μm); RT 2.45 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of 11-oxo-5-propyl-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid (172)

To a stirring solution of compound 171 (700 mg, 2.25 mmol) in THF:H₂O(1:1, 20 mL) was added lithium hydroxide monohydrate (284 mg, 6.76 mmol)at RT; and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. The pHof the residue was acidified to ˜4 with 1 N HCl and stirred for 30 min.The precipitated solid was filtered, washed with water (30 mL) and driedin vacuo to afford compound 172 (550 mg, 82%) as an off-white solid.TLC: 20% EtOAc/hexanes (R_(f). 0.1); ¹H NMR (DMSO-d₆, 500 MHz): 12.81(br s, 1H), 10.30 (s, 1H), 7.68-7.56 (m, 3H), 7.52-7.45 (m, 1H), 7.23(dd, J=9.0, 8.1 Hz, 2H), 7.09 (t, J=7.4 Hz, 1H), 3.71 (br d, J=17.6 Hz,2H), 1.53-1.46 (m, 2H), 0.86 (t, J=7.4 Hz, 3H); LC-MS: 96.38%; 296.9(M⁺+1); (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); RT 2.14 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of 5-butyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid (176): A Common Intermediate

Synthesis of methyl 5-butyl-10-(4-methoxybenzyl)-11-oxo-10,11-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylate (174)

To a stirring solution of methyl10-(4-methoxybenzyl)-11-oxo-10,11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylate 173 (500 mg, 1.28 mmol) in DMF (10 mL) underargon atmosphere were added cesium carbonate (1.25 g, 3.86 mmol), TBAI(cat 10 mg), bromo butane (1.4 mL, 12.8 mmol) in a sealed tube at RT;heated to 110° C. and stirred for 24 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith water and extracted with EtOAc (2×50 mL). The combined organiclayer was washed with water and dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 1% EtOAc/CH₂Cl₂ to affordcompound 174 (300 mg, 28%) as an off white solid. TLC: 5% EtOAc/CH₂Cl₂(R_(f): 0.6); ¹H NMR (400 MHz, DMSO-d₆): δ 7.96 (d, J=1.9 Hz, 1H), 7.69(dd, J=8.5, 1.9 Hz, 1H), 7.59 (dd, J=7.7, 1.6 Hz, 1H), 7.48-7.42 (m,1H), 7.33 (d, J=8.5 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.18-7.09 (m, 3H),6.79 (d, J=8.8 Hz, 2H), 5.60 (d, J=15.6 Hz, 1H), 4.88 (d, J=15.6 Hz,1H), 3.80 (s, 3H), 3.71-3.70 (m, 1H), 3.68 (s, 3H), 3.66-3.60 (m, 1H),1.56-1.49 (m, 1H), 1.41-1.23 (m, 3H), 0.82 (t, J=7.3 Hz, 3H); LC-MS:91.60%; 445.2 (M++1); (column; Ascentis Express C-18 (50×3.0 mm, 2.7μm); RT 3.04 min; 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2mL/min).

Synthesis of methyl 5-butyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1,4] diazepine-8-carboxylate (175)

To a stirring solution of methyl 5-butyl-10-(4-methoxybenzyl)-11-oxo-10,11-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylate 174 (300 mg,0.67 mmol) in trifluoroacetic acid (2 mL) at RT; heated to 60° C. andstirred for 3 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with saturated sodium bicarbonate solution (30 mL) and extractedwith EtOAc (2×25 mL). The combined organic layer was washed with waterand dried over sodium sulfate, filtered and concentrated in vacuo toafford compound 175 (200 mg crude) as an off white solid. TLC: 5%EtOAc/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 10.32 (br s,1H), 7.71-7.64 (m, 2H), 7.61 (dd, J=7.7, 1.6 Hz, 1H), 7.53-7.45 (m, 1H),7.31 (d, J=8.5 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.15-7.09 (m, 1H), 3.81(s, 3H), 3.77-3.58 (m, 2H), 1.58-1.44 (m, 2H), 1.39-1.29 (m, 2H), 0.82(t, J=7.3 Hz, 3H); LC-MS: 89.47%; 325.3 (M⁺+1); (column; X Select CSHC-18, (50×3.0 mm, 2.5 μm); RT 4.26 min; 2.5 mM Aq. NH4OOCH:ACN, 0.8mL/min).

Synthesis of 5-butyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid (176)

To a stirring solution of compound 175 (200 mg, 0.61 mmol) in THF:H₂O(1:1, 10 mL) was added lithium hydroxide monohydrate (78 mg, 1.85 mmol)at RT; heated to 60° C. and stirred for 2.5 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The pH of the residue was acidified to ˜4 with 1 N HCland stirred for 10 min. The precipitated solid was filtered, washed withwater (30 mL), ether (20 mL) and pentane (20 mL) and dried in vacuo toafford compound 176 (110 mg, 58%) as an off-white solid. TLC: 30%EtOAc/hexanes (R_(f): 0.1); ¹H NMR (DMSO-d₆, 400 MHz): δ 12.82 (br s,1H), 10.30 (s, 1H), 7.69-7.61 (m, 3H), 7.54-7.46 (m, 1H), 7.29-7.23 (m,2H), 7.11 (t, J=7.2 Hz, 1H), 3.86-3.64 (m, 2H), 1.55-1.43 (m, 2H),1.40-1.29 (m, 2H), 0.82 (t, J=7.3 Hz, 3H); LC-MS: 99.00%; 311.0 (M⁺+1);(column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); RT 2.28 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of 5-isobutyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid (185): A Common Intermediate

Synthesis of tert-butyl 2-nitrobenzoate (178)

To a stirring solution of 2-nitrobenzoic acid 177 (20 g, 119.67 mmol)t-butanol (540 mL) under argon atmosphere were added Boc-anhydride(78.35 g, 359.02 mmol), DMAP (2.90 g, 23.93 mmol) at 0° C.; warmed to RTand stirred for 24 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. Theresidue was diluted with EtOAc (200 mL), washed with water (100 mL),brine (150 mL). The organic extract was dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 2-5%EtOAc/hexanes to afford compound 178 (19 g, 71%) as colorless syrup.TLC: 10% EtOAc/hexanes (R_(f): 0.6); ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.01(d, J=7.8 Hz, 1H), 7.85-7.75 (m, 3H), 1.50 (s, 9H);

Synthesis of tert-butyl 2-aminobenzoate (179)

To a stirring solution of compound 178 (19 g, 85.11 mmol) in MeOH (200mL) under inert atmosphere was added 10% Pd/C (10 g, 50% wet) at RT andstirred under hydrogen atmosphere (balloon pressure) at RT for 18 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite and washed with MeOH (100mL). The filtrate was concentrated in vacuo to afford compound 179 (17g, crude) as colorless syrup. TLC: 10% EtOAc/hexanes (R_(f): 0.8); ¹HNMR (400 MHz, DMSO-d₆): δ 7.64 (dd, J=8.1, 1.6 Hz, 1H), 7.23-7.18 (m,1H), 6.73 (dd, J=8.4, 0.9 Hz, 1H), 6.56 (br s, 2H), 6.51-6.47 (m, 1H),1.53 (s, 9H);

Synthesis of tert-butyl 4-fluoro-3-nitrobenzoate (181)

To a stirring solution of 4-fluoro-3-nitrobenzoic acid 180 (10 g, 54.05mmol) t-butanol (270 mL) under argon atmosphere were added Boc-anhydride(35 g, 162.16 mmol), DMAP (1.3 g, 10.81 mmol) at 0° C.; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with EtOAc (150 mL), washed with water (75 mL), brine (100 mL).The organic extract was dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography (100-200 mesh) using 2-5%EtOAc/hexanes to afford compound 181 (14 g, crude) as colorless syrup.TLC: 10% EtOAc/hexanes (R_(f): 0.8);

¹H NMR (400 MHz, DMSO-d₆): δ 8.52 (dd, J=7.3, 2.3 Hz, 1H), 8.30-8.26 (m,1H), 7.72 (dd, J=11.0, 8.7 Hz, 1H), 1.47 (s, 9H);

Synthesis of tert-butyl 4-((2-(tert-butoxycarbonyl) phenyl)amino)-3-nitrobenzoate (182)

To a stirring solution of compound 181 (8 g, 42.42 mmol) in dry THF (150mL) under argon atmosphere was added potassium tertbutoxide (82.9 mL,82.90 mmol, 1.0 M sol. In THF) at 0° C. and stirred for 45 min; addedcompound 179 (15 g, 62.23 mmol) at 0° C.; warmed to RT and stirred for16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with ice-cold water (100 mL)and extracted with EtOAc (2×100 mL). The combined organic extracts werewashed with water (100 mL), brine (100 mL) and dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography (100-200mesh) using 100% EtOAc to afford compound 182 (6 g 34%) as yellowliquid. TLC: 10% EtOAc/hexanes (R_(f). 0.8); ¹H NMR (500 MHz, DMSO-d₆):δ 10.94 (s, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.00-7.92 (m, 2H), 7.65-7.54(m, 2H), 7.46 (d, J=9.0 Hz, 1H), 7.30-7.25 (m, 1H), 1.56-1.49 (m, 18H);

Synthesis of tert-butyl 4-((2-(tert-butoxycarbonyl) phenyl)(isobutyl)amino)-3-nitrobenzoate (183)

To a stirring solution of compound 182 (4 g, 9.65 mmol) in DMF (100 mL)under argon atmosphere were added cesium carbonate (6.28 g, 19.32 mmol),TBAI (713 mg, 1.93 mmol), 1-bromo-2-methylpropane (8.4 mL, 48.66 mmol)in a sealed tube at RT; heated to 85° C. and stirred for 16 h. Thereaction was monitored by TLC; after 16 h, the reaction mixture wasdiluted EtOAc (2×75 mL) and washed with water (150 mL), brine (100 mL).The organic extract was dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography (100-200 mesh) using 2-5%EtOAc/hexanes to afford compound 183 (1 g, 22%) as colorless syrup. TLC:10% EtOAc/hexanes (R_(f): 0.5); ¹H NMR (400 MHz, DMSO-d₆): δ 7.98 (dd,J=8.9, 2.1 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.59-7.52 (m, 1H), 7.46 (d,J=8.9 Hz, 1H), 7.40 (dd, J=7.8, 1.6 Hz, 1H), 7.33 (dd, J=8.2, 0.8 Hz,1H), 7.18 (td, J=7.5, 1.0 Hz, 1H), 3.67 (d, J=7.4 Hz, 2H), 2.13-2.05 (m,1H), 1.49 (s, 9H), 1.14 (s, 9H), 0.98 (d, J=6.7 Hz, 6H);

Synthesis of tert-butyl 3-amino-4-((2-(tert-butoxycarbonyl) phenyl)(isobutyl) amino) benzoate (184)

To a stirring solution of compound 183 (1.5 g, 3.19 mmol) in MeOH (100mL) under inert atmosphere was added 10% Pd/C (1.5 g, 50% wet) at RT andstirred under hydrogen atmosphere (balloon pressure) at RT for 5 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite and washed with MeOH (100mL). The filtrate was concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 5-10%EtOAc/hexanes to afford compound 184 (1.4 g, quantitative) as colorlesssyrup. TLC: 10% EtOAc/hexanes (R_(f): 0.5); ¹H NMR (500 MHz, DMSO-d₆): δ7.42 (dd, J=7.5, 1.2 Hz, 1H), 7.35-7.29 (m, 1H), 7.21 (d, J=2.3 Hz, 1H),7.10 (dd, J=8.4, 2.0 Hz, 1H), 7.02 (t, J=7.2 Hz, 1H), 6.93 (dd, J=11.6,8.1 Hz, 2H), 5.13 (s, 2H), 3.17 (d, J=7.5 Hz, 2H), 1.86-1.8-0 (m, 1H),1.49 (s, 9H), 1.42 (s, 9H), 0.83 (d, J=7.0 Hz, 6H);

Synthesis of 5-isobutyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid (185)

To a stirring solution of compound 184 (1 g, 2.27 mmol) in 1,2-dichloroethane (25 mL) under inert atmosphere was addedtrifluoroacetic acid (3.5 mL, 45.55 mmol) at 0° C.; heated to 80° C. andstirred for 9 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The pH of the residuewas adjusted to ˜8 using saturated sodium bicarbonate solution (10 mL),washed with EtOAc (2×75 mL). The pH of the aqueous layer was adjusted to˜1 with 1 N HCl and extracted with EtOAc (2×50 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to afford compound 185 (500 mg, 60%) as brown solid. TLC: 30%EtOAc/hexanes (R_(f): 0.2); ¹H NMR (400 MHz, DMSO-d₆): δ 12.81 (br s,1H), 10.31 (s, 1H), 7.69-7.59 (m, 3H), 7.52-7.45 (m, 1H), 7.28 (d, J=8.4Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.14-7.07 (m, 1H), 3.63-3.46 (m, 2H),1.83-1.70 (m, 1H), 0.89 (d, J=6.5 Hz, 6H);

Synthesis of 5-allyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid (190): A Common Intermediate

Synthesis of methyl 11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylate (186)

To a stirring solution of 11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1, 4]diazepine-8-carboxylic acid 163 (4.5 g, 17.71 mmol) in 50% MeOH/CH₂Cl₂under argon atmosphere was added diazomethane in diethyl ether (freshlyprepared by addition of N-nitrosomethyl urea (9.1 g, 88.58 mmol) tomixture of 50% KOH solution (100 mL) and diethylether (200 mL) at 0° C.)at 0° C.; warmed to RT and stirred for 3 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 2% MeOH/CH₂Cl₂ to afford compound 186 (3 g,64%) as an off white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.6); ¹H NMR(400 MHz, DMSO-d₆): δ 9.94 (s, 1H), 8.32 (s, 1H), 7.71 (dd, J=7.9, 1.6Hz, 1H), 7.60-7.53 (m, 2H), 7.38-7.34 (m, 1H), 7.06 (d, J=8.3 Hz, 1H),7.02-6.98 (m, 1H), 6.95-6.89 (m, 1H), 3.79 (s, 3H); LC-MS: 87.13%; 269.0(M⁺+1); (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); RT 2.05 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of methyl 10-(4-methoxybenzyl)-11-oxo-10,11-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylate (173)

To a stirring solution of methyl 11-oxo-10, 11-dihydro-5H-dibenzo [b, e][1, 4] diazepine-8-carboxylate 186 (3 g, 11.19 mmol) in DMF (30 mL)under inert atmosphere were added Cs₂CO₃ (4.3 g, 13.43 mmol), PMBCl (2.1g, 13.43 mmol) at 0° C.; warmed to RT and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with ice cold water and extracted with EtOAc (2×25mL). The combined organic extracts were washed with water (100 ml) anddried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 2% EtOAc/CH₂Cl₂ to afford compound 173 (1.7 g, 40%)as an off white solid. TLC: 5% EtOAc/CH₂Cl₂ (R_(f): 0.6); ¹H NMR (400MHz, DMSO-d₆): δ 8.32 (s, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.68 (dd, J=7.8,1.4 Hz, 1H), 7.62 (dd, J=8.3, 1.9 Hz, 1H), 7.41-7.35 (m, 1H), 7.20-7.18(m, 3H), 7.09 (d, J=7.5 Hz, 1H), 7.05-6.99 (m, 1H), 6.84 (d, J=8.7 Hz,2H), 5.16 (s, 2H), 3.77 (s, 3H), 3.70 (s, 3H); LC-MS: 94.69%; 389.1(M⁺+1); (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); RT 2.55 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of methyl 5-allyl-10-(4-methoxybenzyl)-11-oxo-10,11-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylate (188)

To a stirring solution of methyl 10-(4-methoxybenzyl)-11-oxo-10,11-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylate 173 (600 mg,1.54 mmol) in DMF (10 mL) under argon atmosphere were added cesiumcarbonate (1.5 g, 4.63 mmol), TBAI (0.057 mg, 0.15 mmol),3-bromoprop-1-ene (1.3 mL, 15.4 mmol) in a sealed tube at RT; heated to120° C. and stirred for 24 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with icecold water (50 mL) and extracted with EtOAc (2×25 mL). The combinedorganic extracts were washed with water (100 mL) and dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 2%EtOAc/hexanes to afford compound 188 (555 mg, 84%) as an off-whitesolid. TLC: 5% EtOAc/hexanes (R_(f): 0.6); ¹H NMR (DMSO-d₆, 400 MHz): δ7.95 (d, J=1.9 Hz, 1H), 7.67 (dd, J=8.5, 1.9 Hz, 1H), 7.61 (dd, J=7.7,1.6 Hz, 1H), 7.48-7.42 (m, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.23-7.10 (m,4H), 6.81 (d, J=8.7 Hz, 2H), 5.71-5.57 (m, 2H), 5.30 (dd, J=17.3, 1.5Hz, 1H), 5.12 (dd, J=10.4, 1.4 Hz, 1H), 4.91 (d, J=15.6 Hz, 1H), 4.41(t, J=5.7 Hz, 2H), 3.79 (s, 3H), 3.69 (s, 3H); LC-MS: 96.23%; 429.1(M⁺+1); (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); RT 2.81 min;0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of methyl 5-allyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1,4] diazepine-8-carboxylate (189)

A mixture of methyl 5-allyl-10-(4-methoxybenzyl)-11-oxo-10,11-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylate 188 (550 mg,1.28 mmol) in trifluoroacetic acid (3 mL) at RT was heated to 60° C. andstirred for 1.5 h. The reaction was monitored by TLC; after completionof the reaction, the volatiles were removed in vacuo. The residue wasdiluted with saturated sodium bicarbonate solution (30 mL) and extractedwith EtOAc (2×25 mL). The combined organic layer was washed with waterand dried over sodium sulfate, filtered and concentrated in vacuo toafford compound 189 (300 mg, 76%) as an off-white solid. TLC: 30%EtOAc/CH₂Cl₂ (R_(f): 0.3); ¹H NMR (500 MHz, DMSO-d₆): δ 10.38 (s, 1H),7.70-7.66 (m, 2H), 7.62 (dd, J=7.7, 1.3 Hz, 1H), 7.51-7.46 (m, 1H), 7.29(d, J=9.0 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H),5.79-5.65 (m, 1H), 5.33 (dd, J=17.2, 1.0 Hz, 1H), 5.14 (d, J=9.5 Hz,1H), 4.48-4.44 (m, 2H), 3.81 (s, 3H); LC-MS: 99.27%; 309.0 (M⁺+1);column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); RT 2.36 min; 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of 5-allyl-11-oxo-10, 11-dihydro-5H-dibenzo [b, e] [1,4]diazepine-8-carboxylic acid (190)

To a stirring solution of compound 189 (300 mg, 0.97 mmol) in THF:H₂O(1:1, 15 mL) was added lithium hydroxide monohydrate (122 mg, 2.92 mmol)at RT; heated to 70° C. and stirred for 2 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo. The pH of the residue was acidified to ˜4 with 1 N HCl andstirred for 15 min. The precipitated solid was filtered, washed withwater (40 mL), diethylether (20 mL) and pentane (20 mL) and dried invacuo to afford compound 190 (200 mg, 70%) as an off-white solid. TLC:50% EtOAc/hexanes (R_(f): 0.1); ¹H NMR (400 MHz, DMSO-d₆): δ 12.85 (brs, 1H), 10.35 (s, 1H), 7.67-7.59 (m, 3H), 7.52-7.44 (m, 1H), 7.26 (d,J=8.9 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.11 (t, J=7.2 Hz, 1H), 5.80-5.66(m, 1H), 5.33 (dd, J=17.3, 1.6 Hz, 1H), 5.14 (dd, J=10.4, 1.4 Hz, 1H),4.45 (d, J=2.4 Hz, 2H); LC-MS: 96.58%; 294.9 (M⁺+1); (column; AscentisExpress C-18 (50×3.0 mm, 2.7 μm); RT 2.06 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of 5-(2-hydroxyethyl)-11-oxo-10, 11-dihydro-5H-dibenzo [b, e][1, 4] diazepine-8-carboxylic acid (194): A Common Intermediate

Synthesis of methyl 10-(4-methoxybenzyl)-11-oxo-5-(2-oxoethyl)-10,11-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylate (191)

To a stirring solution of methyl 5-allyl-10-(4-methoxybenzyl)-11-oxo-10,11-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylate 188 (500 mg,1.16 mmol) in 1, 4 dioxane:H₂O (1:1:2, 40 mL) was added 2, 6-lutidine(0.27 mL, 2.30 mmol) at 25° C. followed by addition of osmium tetroxide(3.75 mL, 0.058 mmol, 0.4% solution in t-butanol), sodium metaperiodate(1 g, 4.67 mmol) and stirred at RT for 16 h. The reaction was monitoredby TLC; after completion the reaction mixture was quenched with ice-coldwater (10 mL) and extracted with CH₂Cl₂ (2×75 mL). The combined organicextracts were dried over sodium and concentrated in vacuo to affordcrude compound 191 (600 mg) as pale brown solid. TLC: 30% EtOAc/hexanes(R_(f): 0.4); LC-MS: 40.34%; 431.0 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 2.53 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min).

Synthesis of methyl 5-(2-hydroxyethyl)-10-(4-methoxybenzyl)-11-oxo-10,11-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylate (192)

To a stirring solution of methyl10-(4-methoxybenzyl)-11-oxo-5-(2-oxoethyl)-10, 11-dihydro-5H-dibenzo [b,e] [1, 4] diazepine-8-carboxylate 191 (1.15 g, crude) in MeOH (30 mL)under argon atmosphere was added sodium borohydride (203 mg, 5.34 mmol)at 0° C.; warmed to RT and stirred for 4 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasdiluted with water (50 mL) and extracted with CH₂Cl₂ (2×100 mL). Thecombined organic extracts were dried over sodium sulfate andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silicagel column chromatography (100-200 mesh) using 40-50%EtOAc/hexanes to afford compound 192 (400 mg, 40%, over 2 steps) as anoff-white solid. TLC: 40% EtOAc/hexanes (R_(f): 0.2); ¹H NMR (400 MHz,DMSO-d₆): δ 7.92 (d, J=1.8 Hz, 1H), 7.67 (dd, J=8.5, 1.9 Hz, 1H), 7.61(dd, J=7.7, 1.6 Hz, 1H), 7.49-7.44 (m, 1H), 7.36 (d, J=8.5 Hz, 1H),7.27-7.21 (m, 3H), 7.16-7.10 (m, 1H), 6.80 (d, J=8.9 Hz, 2H), 5.64 (d,J=15.7 Hz, 1H), 4.89 (d, J=15.9 Hz, 1H), 4.76 (t, J=5.3 Hz, 1H),3.91-3.80 (m, 2H), 3.78 (s, 3H), 3.68 (s, 3H), 3.56-3.48 (m, 2H); LC-MS:94.51%; 432.1 (M⁺+1); (column; Ascentis Express C-18, (50×3.0 mm, 2.7μm); RT 2.35 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min);

Synthesis of methyl 11-oxo-5-(2-(2, 2, 2-trifluoroacetoxy) ethyl)-10,11-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylate (193)

A mixture of methyl 5-(2-hydroxyethyl)-10-(4-methoxybenzyl)-11-oxo-10,11-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylate 192 (400 mg,0.92 mmol) in trifluoroacetic acid (0.11 mL, 1.51 mmol) under inertatmosphere at RT was heated to 60° C. and stirred for 3 h. The reactionwas monitored by TLC; after completion of the reaction, the volatileswere removed in vacuo to obtain the crude. The residue was diluted withCH₂Cl₂ (100 mL) and washed with saturated sodium bicarbonate solution(30 mL). The organic extracts were dried over sodium sulfate andconcentrated in vacuo to afford 203 (450 mg, mixture of 193 (major) &193A (minor)) as an off-white solid. TLC: 40% EtOAc/hexanes (R_(f):0.8); LC-MS: 80.01%; 409.0 (M⁺+1), 12.26%; 313.1 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.40 min, 1.91 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of 5-(2-hydroxyethyl)-11-oxo-10, 11-dihydro-5H-dibenzo [b, e][1, 4] diazepine-8-carboxylic acid (194)

To a stirring solution of compound 193 & 193A (430 mg, mixture ofcompounds) in THF:H₂O (1:1, 14 mL) was added lithium hydroxidemonohydrate (221 mg, 5.26 mmol) portion wise for 10 min at RT andstirred for 24 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The pH of the residuewas acidified with 2 M HCl to ˜1. The obtained solid was filtered anddried in vacuo to afford compound 194 (250 mg, 80%) as an off-whitesolid. TLC: 50% EtOAc/hexanes (R_(f): 0.1); ¹H NMR (400 MHz, DMSO-d₆): δ12.84 (br s, 1H), 10.30 (s, 1H), 7.68-7.59 (m, 3H), 7.54-7.47 (m, 1H),7.29-7.23 (m, 2H), 7.14-7.08 (m, 1H), 4.66 (t, J=4.6 Hz, 1H), 3.89-3.79(m, 2H), 3.54-3.48 (m, 2H); LC-MS: 92.62%; 298.9 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.66 min, 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of 6-oxo-6, 11-dihydro-5H-dibenzo [b, e] azepine-3-carboxylicacid (210): A Common Intermediate

Synthesis of ethyl 4-(2-(methoxycarbonyl) benzyl)-3-nitrobenzoate (197)

To a stirring solution of methyl 2-(bromomethyl) benzoate 195 (9 g,39.30 mmol) in 1, 2 dimethoxy ethane (72 mL) was added Pd(PPh₃)₄ (1.81g, 1.57 mmol) and purged under argon atmosphere for 10 min. To this wereadded (4-(ethoxycarbonyl)-2-nitrophenyl) boronic acid 196 (10.6 g, 44.41mmol) dissolved in 1, 2 dimethoxy ethane:EtOH (2:1, 108 mL) and 2 Msodium carbonate solution (72 mL) and purged under argon atmosphere for15 min at RT and stirred for 2 h. The reaction was monitored by TLC;after completion the reaction the volatiles were removed in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 2-6% EtOAc/hexanes to afford compound 197 (5.6 g,41%) as an off-white solid. TLC: 10% EtOAc/hexanes (R_(f): 0.3); ¹H-NMR(DMSO-d₆, 400 MHz): δ 8.45 (s, 1H), 8.11 (dd, J=8.1, 1.8 Hz, 1H), 7.93(dd, J=7.8, 1.4 Hz, 1H), 7.59 (td, J=7.5, 1.5 Hz, 1H), 7.45 (td, J=7.6,1.1 Hz, 1H), 7.29 (d, J=7.1 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 4.63 (s,2H), 4.36 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 1.33 (t, J=7.1 Hz, 3H).

Synthesis of 4-(2-carboxybenzyl)-3-nitrobenzoic acid (198)

To a stirring solution of compound 197 (5.6 g, 16.23 mmol) in THF:H₂O(4:1, 615 mL) was added lithium hydroxide monohydrate (6.82 g, 162.31mmol) portion wise for 10 min at RT heated to 60° C. and stirred for 2h. The reaction was monitored by TLC; after completion of the reaction,the volatiles were removed in vacuo. The pH of the residue was acidifiedwith 2 N HCl to ˜1. The obtained solid was filtered and dried in vacuoto obtain compound 198 (3.2 g, 66%) as yellow solid. TLC: 10%EtOAc/hexanes (R_(f): 0.1); ¹H-NMR (CD₃OD-d₄, 400 MHz): δ 8.34 (s, 1H),8.00 (d, J=8.0 Hz, 1H), 7.65-7.64 (m, 1H), 7.63 (t, J=6.0 Hz, 1H), 7.53(t, J=6.0 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 4.70(s, 2H).

Synthesis of 3-amino-4-(2-carboxybenzyl) benzoic acid (199)

To a stirring solution of compound 198 (1 g, 3.32 mmol) in MeOH (20 mL)under inert atmosphere was added 10% Pd/C (200 mg) at RT and stirredunder hydrogen atmosphere (balloon pressure) at RT for 18 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite and washed with MeOH (100mL). The filtrate was concentrated in vacuo to obtain the crude. Thecrude washed with diethyl ether (30 mL) and dried in vacuo to affordcompound 199 (830 mg, 92%) as pale brown solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 12.48 (br s, 1H), 7.81 (d,J=7.4 Hz, 1H), 7.43 (t, J=7.3 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.24 (s,1H), 7.13 (d, J=7.5 Hz, 1H), 7.02 (dd, J=7.8, 1.4 Hz, 1H), 3.17 (s, 2H);LC-MS: 91.07%; 271.9 (M⁺+1); (column; X Select CSH C-18, (50×3.0 mm, 3.5μm); RT 2.51 min. 0.05% Aq. TFA: ACN, 0.8 mL/min).

Synthesis of 6-oxo-6, 11-dihydro-5H-dibenzo [b, e] azepine-3-carboxylicacid (200)

To a stirring solution of compound 199 (830 mg, 3.06 mmol) in THF (20mL) under inert atmosphere was added CDI (2.02 g, 12.25 mmol) at RT andstirred for 18 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The pH of the residuewas adjusted to ˜2 using 4 N HCl. The precipitated solid was filtered,washed with and dried in vacuo to afford compound 200 (515 mg, 66%) asan off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R₁ 0.3); ¹H NMR (DMSO-d₆, 400MHz): δ 12.93 (br s, 1H), 10.57 (s, 1H), 7.74-7.67 (m, 2H), 7.64 (dd,J=7.8, 1.7 Hz, 1H), 7.52-7.44 (m, 2H), 7.42-7.38 (m, 1H), 7.34 (tdJ=7.5, 1.3 Hz, 1H), 3.98 (s, 2H); LC-MS: 99.31%; 253.9 (M⁺+1); (column;X Select CSH C-18, (50×3.0 mm, 3.5 μm); RT 2.75 min. 0.05% Aq. TFA: ACN,0.8 mL/min).

Synthesis of 11-methyl-6-oxo-6, 11-dihydro-5H-dibenzo [b, e]azepine-3-carboxylic acid (211): A Common Intermediate

Synthesis of methyl 2-bromobenzoate (202)

To a stirring solution of 2-bromobenzoic acid 201 (15 g, 74.62 mmol) inMeOH (150 mL) under inert atmosphere was added concentrated sulfuricacid (4 mL, 75.04 mmol) dropwise for 5 min at 0° C.; heated to refluxand stirred for 18 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. Theresidue was diluted with ice-cold water (100 mL) and extracted withEtOAc (2×100 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to afford compound 202 (14g, 93%) as colorless syrup. TLC: 10% EtOAc/hexanes (R_(f): 0.5). ¹H NMR(CDCl₃, 400 MHz): δ 7.81-7.77 (m, 1H), 7.70-7.64 (m, 1H), 7.39-7.30 (m,2H), 3.94 (s, 3H).

Synthesis of methyl 2-((trimethylsilyl) ethynyl) benzoate (203)

To a stirring solution of methyl 2-bromobenzoate 202 (14 g, 65.11 mmol)in THF (150 mL) under inert atmosphere were added triphenylphosphine(426 mg, 1.62 mmol), Pd(PPh₃)₂Cl₂ (4.57 g, 6.51 mmol),ethynyltrimethylsilane (18.4 mL, 130.23 mmol), triethyl amine (18.7 mL,130.2 mmol) and purged under argon for 15 min. To this was added copperiodide (1.23 g, 6.51 mmol) at RT and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas filtered through celite washed with EtOAc (200 mL). The filtrate waswashed with water (150 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 2% EtOAc/hexanes toafford compound 203 (11 g, 73%) a colorless syrup. TLC: 5% EtOAc/hexanes(R_(f): 0.5); ¹H NMR (CDCl₃, 400 MHz) δ 7.92-7.88 (m, 1H), 7.60-7.55 (m,1H), 7.44 (td, J=7.6, 1.5 Hz, 1H), 7.36 (td, J=7.6, 1.3 Hz, 1H), 3.92(s, 3H), 0.27 (s, 9H).

Synthesis of methyl 2-ethynylbenzoate (204)

To a stirring solution of compound 203 (45 g, 193.96 mmol) in MeOH (500mL) under inert atmosphere was added potassium carbonate (40 g, 290.94mmol) at RT and stirred for 4 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was filteredthrough celite washed with CH₂Cl₂ (2×500 mL). The filtrate was removedin vacuo to obtain the crude. The crude was as purified through silicagel column chromatography using 2% EtOAc/hexanes to afford compound 204(31 g, 33%) as colorless syrup. TLC: 5% EtOAc/hexanes (R_(f): 0.5); ¹HNMR (CDCl₃, 400 MHz): δ 7.97-7.91 (m, 1H), 7.62 (dd, J=7.7, 1.1 Hz, 1H),7.47 (td, J=7.6, 1.5 Hz, 1H), 7.40 (td, J=7.7, 1.4 Hz, 1H), 3.38 (s,1H), 3.91 (s, 3H).

Synthesis of methyl 2-(1-(tributylstannyl) vinyl) benzoate (205)

To a stirring solution of compound 204 (10 g, 62.5 mmol) andPd(PPh₃)₂Cl₂ (877 mg, 1.25 mmol) in THF (37 mL) under inert atmospherewas added tributyltin hydride (20.43 mL, 75 mmol) at RT and stirred for2.5 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 2%EtOAc/hexanes to afford compound 205 (28 g, 54%) as colorless syrup.TLC: 5% EtOAc/hexanes (R_(f): 0.8); ¹H NMR (CDCl₃, 400 MHz): δ 7.87 (dd,J=7.8, 0.9 Hz, 1H), 7.41 (td, J=7.6, 1.4 Hz, 1H), 7.21 (td, J=7.6, 1.3Hz, 1H), 7.01 (dd, J=7.7, 0.9 Hz, 1H), 5.67 (d, J=2.8 Hz, 1H), 5.38 (d,J=2.9 Hz, 1H), 3.82 (s, 3H), 1.49-1.39 (m, 6H), 1.30-1.20 (m, 6H),0.90-0.83 (m, 15H).

Synthesis of methyl 4-iodo-3-nitrobenzoate (207)

To a stirring solution of 4-iodo-3-nitrobenzoic acid 206 (15 g, 51.36mmol) in MeOH (150 mL) under inert atmosphere was added concentratedsulphuric acid (15 mL) dropwise for 10 min at 0° C.; warmed to RT atstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with ice-cold water (500 mL) and extracted with EtOAc (3×100mL). The combined organic extracts were washed saturated sodiumbicarbonate solution (2×100 mL) dried over sodium sulfate, filtered andconcentrated in vacuo to afford compound 207 (13 g, 83%) as an off-whitesolid. TLC: 30% EtOAc/hexanes (R_(f): 0.8); ¹H NMR (CDCl₃, 500 MHz) δ8.45 (s, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.88 (dd, J=8.2, 1.9 Hz, 1H), 3.97(s, 3H).

Synthesis of methyl 4-(1-(2-(methoxycarbonyl) phenyl)vinyl)-3-nitrobenzoate (208)

To a stirring solution of compound 205 (25 g, 5.52 mmol) in 1, 4-dioxane(40 mL) under inert atmosphere in a sealed tube were added methyl4-iodo-3-nitrobenzoate 207 (1.86 g, 6.08 mmol), lithium chloride (813mg, 19.35 mmol) and purged under argon for 20 min. To this was addedPd(dppf)Cl₂ (2 g, 2.76 mmol) at RT; heated to 120° C. and stirred for 16h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was filtered through celite washed with EtOAc (2×50mL). The filtrate was washed with water (2×50 mL), dried over sodiumsulfate, filtered and concentrated in vacuo to afford compound 208 (1.3g, 70%) colorless syrup. TLC: 20% EtOAc/hexanes (R_(f): 0.4); ¹H-NMR(CDCl₃, 400 MHz): δ 8.30 (s, 1H), 8.17 (dd, J=8.2, 1.8 Hz, 1H),7.69-7.65 (m, 2H), 7.52-7.42 (m, 2H), 7.40-7.35 (m, 1H), 5.61 (s, 1H),5.58 (s, 1H), 3.96 (s, 3H), 3.58 (s, 3H).

Synthesis of methyl 3-amino-4-(1-(2-(methoxycarbonyl) phenyl) ethyl)benzoate (209)

To a stirring solution of compound 208 (100 g, 0.29 mmol) in MeOH (10mL) under inert atmosphere was added 10% Pd/C (40 mg, dry) at RT andstirred under hydrogen atmosphere (balloon pressure) for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite, washed with CH₂Cl₂ (2×50mL). The filtrate was concentrated in vacuo to afford compound 209 (70mg, 77%) as colorless syrup. TLC: 20% EtOAc/hexanes (R_(f): 0.7); ¹H-NMR(DMSO-d₆, 500 MHz): δ 7.68 (dd, J=7.8, 1.2 Hz, 1H), 7.46 (td, J=7.6, 1.4Hz, 1H), 7.32 (td, J=7.5, 1.0 Hz, 1H), 7.24 (s, 1H), 7.21-7.15 (m, 2H),7.14-7.10 (m, 1H), 5.09 (s, 2H), 4.85 (q, J=6.9 Hz, 1H), 3.79 (s, 6H),1.46 (d, J=7.0 Hz, 3H).

Synthesis of 3-amino-4-(1-(2-carboxyphenyl) ethyl) benzoic acid (210)

To a stirring solution of compound 209 (1.4 g, 4.47 mmol) in THF:H₂O(4:1, 20 mL) was added lithium hydroxide monohydrate (1.07 g, 22.3 mmol)at RT and heated to 70° C. and stirred for 6 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The pH of the residue was acidified with 2 N HCl to˜4. The precipitated solid was filtered, washed with water (50 mL),n-pentane (30 mL) and dried in vacuo to afford compound 210 (900 mg,71%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR(DMSO-d₆, 500 MHz): δ 12.50 (br s, 1H), 7.70 (dd, J=7.8, 1.2 Hz, 1H),7.40 (td, J=7.6, 1.3 Hz, 1H), 7.28-7.23 (m, 2H), 7.19-7.17 (m, 2H), 7.09(d, J=7.8 Hz, 1H), 4.98 (q, J=6.9 Hz, 1H), 1.44 (d, J=6.9 Hz, 3H).

Synthesis of 11-methyl-6-oxo-6, 11-dihydro-5H-dibenzo [b, e]azepine-3-carboxylic acid (211)

To a stirring solution of compound 210 (900 mg, 3.15 mmol) in THF (20mL) under inert atmosphere was added CDI (2.5 g, 15.7 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with water (15 mL) and pH was adjusted to ˜4 with 2 N HCl. Theobtained solid was filtered washed with water (30 mL), diethyl ether (20mL) and dried in vacuo to afford compound 211 (750 mg, 89%) as anoff-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.3); LC-MS: 96.89%; 267.9(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.14 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 6, 11-dioxo-6, 11-dihydro-5H-dibenzo [b, e]azepine-3-carboxylic acid (216): A Common Intermediate

Synthesis of methyl 4-(2-(methoxycarbonyl) benzoyl)-3-nitrobenzoate(213)

To a stirring solution of methyl 4-(1-(2-(methoxycarbonyl) phenyl)vinyl)-3-nitrobenzoate 212 (8 g, 23.46 mmol) in a mixture of CH₂Cl₂:H₂O(1:1, 500 mL) were added KMNO₄ (37 g, 234.6 mmol), tetrabutylammoniumhydrogensulfate (7.9 g, 23.46 mmol), sodium bicarbonate (9.8 g, 117.3mmol) at RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was quenched withacetic acid (20 mL) and 10% sodium bisulfate solution (50 mL) andextracted with CH₂Cl₂ (2×500 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo. The crudewas purified through silica gel column chromatography using 40%EtOAc/hexanes to afford compound 213 (4 g, 50%) as colorless syrup. TLC:30% EtOAc/hexanes (R_(f): 0.5); ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.55 (s,1H), 8.34 (dd, J=18.0, 1.6 Hz, 1H), 7.82-7.65 (m, 4H), 7.56 (d, J=7.5Hz, 1H), 3.94 (s, 3H), 3.70 (s, 3H).

Synthesis of methyl 3-amino-4-(2-(methoxycarbonyl) benzoyl) benzoate(214)

To a stirring solution of compound 213 (4 g, 11.66 mmol) in a mixture ofEtOH:H₂O (1:1, 60 mL) were added iron powder (6.5 g, 116.48 mmol) andammonium chloride (6.1 g, 115.09 mmol) at RT; heated to 90° C. andstirred for 4 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with CH₂Cl₂ (200 mL),filtered through celite, washed with 20% MeOH/CH₂Cl₂ (50 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 1% MeOH/CH₂Cl₂ (50 mL) toafford compound 214 (2 g, 56%) as pale green solid. TLC: 20% MeOH/CH₂Cl₂(R_(f): 0.7); ¹H-NMR (DMSO-d₆, 500 MHz): δ 7.99 (d, J=7.8 Hz, 1H), 7.75(dd, J=7.8, 1.2 Hz, 1H), 7.65 (td, J=7.8, 1.2 Hz, 1H), 7.51 (s, 1H),7.47-7.41 (m, 3H), 6.98 (d, J=8.4 Hz, 1H), 6.90 (dd, J=8.4, 1.4 Hz, 1H),3.62 (s, 3H), 3.31 (s, 3H).

Synthesis of 3-amino-4-(2-carboxybenzoyl) benzoic acid (215)

To a stirring solution of compound 214 (2 g, 6.38 mmol) in THF:H₂O (4:1,30 mL) was added lithium hydroxide monohydrate (1.34 g, 31.94 mmol) at0° C.; warmed to RT and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The pH of the residue was acidified with 2 N HCl to ˜4. Theprecipitated solid was filtered washed with water (50 mL), trituratedwith diethyl ether (2×20 mL) and dried in vacuo to afford compound 215(1.5 g 84%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2);¹H-NMR (DMSO-d₆, 500 MHz): δ 13.04 (br s, 2H), 7.97 (d, J=7.5 Hz, 1H),7.72-7.67 (m, 1H), 7.63-7.59 (m, 1H), 7.45 (s, 1H), 7.41 (br s, 2H),7.35 (d, J=7.5 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.89 (dd, J=8.4, 1.4 Hz,1H).

Synthesis of 6, 11-dioxo-6, 11-dihydro-5H-dibenzo [b, e]azepine-3-carboxylic acid (216)

To a stirring solution of compound 215 (750 mg, 2.63 mmol) in THF (20mL) under inert atmosphere was added CDI (2.13 g, 13.15 mmol) 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The residue was diluted with ice-cold water (15 mL) and the pH wasadjusted to ˜4 with 2 N HCl. The obtained solid was filtered washed withwater (30 mL), diethylether (20 mL) and dried in vacuo to affordcompound 216 (600 mg, 86%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.3); ¹H-NMR (DMSO-d₆, 500 MHz): δ 13.30 (br s, 1H), 11.25 (s,1H), 8.19 (d, J=6.4 Hz, 1H), 7.96 (s, 1H), 7.89-7.79 (m, 4H), 7.72 (d,J=8.1 Hz, 1H).

Amines for Compounds:

Commercial Amines Used in the Preparation of Compounds:

Preparation of the Amines:

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl) benzonitrile hydrochloride(227)

Synthesis of 5-(azidomethyl)-2-chlorothiazole (222)

To a stirring solution of 2-chloro-5-(chloromethyl) thiazole 221 (10 g,59.52 mmol) in EtOH (150 mL) under argon atmosphere was added sodiumazide (5.8 g, 89.23 mmol) at RT and heated to reflux for 4 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered, washed with EtOAc (100 mL) and thefiltrate was concentrated in vacuo to obtain the crude. The crude waspurified through silica gel flash column chromatography using 5%EtOAc/hexanes to afford compound 222 (10 g, 97%) as pale yellow oil.TLC: 10% EtOAc/hexanes (R_(f): 0.5); LC-MS: 99.33%; 174.7 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.28 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-chlorothiazol-5-yl) methanamine (223)

To a stirring solution of compound 222 (10 g, 57.47 mmol) in THF:H₂O(15:1, 160 mL) was added triphenyl phosphine (15.05 g, 57.45 mmol)portion wise for 15 min at RT and stirred for 3 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The residue was diluted with EtOAc (3×100 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude compound 223 (10 g) as anoff-white solid; which was carried forward for next step without furtherpurification. TLC: 10% EtOAc/hexanes (R_(f): 0.2). LC-MS: 21.47%+7.59%;149.0 (M⁺+1); (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); RT 0.73min & 0.82 min. 2.5 mM NH4OOCH (Aq)+5% ACN: ACN+5% 2.5 mM NH4OOCH (Aq);0.8 mL/min).

Synthesis of tert-butyl ((2-chlorothiazol-5-yl) methyl) carbamate (224)

To a stirring solution of compound 223 (10 g, 67.56 mmol) in CH₂Cl₂ (150mL) under argon atmosphere were added triethylamine (19.48 mL, 135.05mmol) at 0° C. and stirred for 10 min. To this was added Boc-anhydride(17.67 g, 81.05 mmol) at the same temperature; warmed to RT and stirredfor 16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with water (200 mL) andextracted with CH₂Cl₂ (3×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel flash columnchromatography using 10-20% EtOAc/hexanes to afford compound 224 (8 g,56% over 2 steps) as pale yellow liquid. TLC: 20% EtOAc/hexanes (R_(f):0.8); ¹H-NMR (DMSO-d₆, 400 MHz): δ 7.57 (d, J=4.0 Hz, 1H), 7.49 (s, 1H),4.24 (d, J=6.1 Hz, 2H), 1.39 (s, 9H).

Synthesis of tert-butyl ((2-(4-cyanophenyl) thiazol-5-yl) methyl)carbamate (226)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (1 g, 4.02 mmol) in 1, 2 dimethoxy ethane:H2O (4:1, 30 mL)were added sodium carbonate (1.49 g, 14.08 mmol), (4-cyanophenyl)boronic acid 225 (710 mg, 4.82 mmol) and purged under argon atmospherefor 30 min. To this was added Pd(PPh3)4 (464 mg, 0.40 mmol) at RT;heated to 100° C. and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was pouredinto ice-cold water (100 mL) and extracted with EtOAc (2×150 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude purified throughsilicagel column chromatography using 30% EtOAc/hexanes to affordcompound 226 (550 mg, 43%) as an off-white solid. TLC: 30% EtOAc/hexanes(Rf: 0.3); 1H NMR (DMSO-d6, 500 MHz): δ 8.08 (d, J=8.5 Hz, 2H), 7.95 (d,J=8.6 Hz, 2H), 7.81 (s, 1H), 7.61 (t, J=5.9 Hz, 1H), 4.37 (d, J=5.9 Hz,2H), 1.40 (s, 9H); LC-MS: 97.93%; 315.9 (M++1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.52 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl) benzonitrile hydrochloride(227)

To a stirring solution of compound 226 (550 mg, 1.74 mmol) in CH₂Cl₂ (10mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (5 mL) at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was washed with EtOAc (2×10 mL) anddried in vacuo to afford compound 227 (400 mg, 92%) as an off-whitesolid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ8.68 (br s, 3H), 8.12 (s, 1H), 8.10 (d, J=4.3 Hz, 2H), 7.98 (d, J=8.4Hz, 2H), 4.38 (q, J=5.4 Hz, 2H); LC-MS: 98.49%; 215.9 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.43 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(aminomethyl) thiazol-2-amine dihydrochloride (230)

Synthesis of tert-butyl ((2-((tert-butoxycarbonyl) amino) thiazol-5-yl)methyl) carbamate (229)

To a stirring solution of 2-aminothiazole-5-carbonitrile 228 (300 mg,2.40 mmol) in MeOH (50 mL) were added Boc-anhydride (1.5 mL, 7.20 mmol),nickel (II) chloride (571 mg, 2.40 mmol) at 0° C. To this was addedsodium borohydride (638 mg, 16.80 mmol) portion wise for 10 min at 0°C.; warmed to RT and stirred for 18 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The residue was diluted with EtOAc (100 mL) and water (75 mL),filtered through celite. The organic layer was dried over sodiumsulphate, filtered and concentrated in vacuo to obtain compound 229 (300mg) as colorless syrup. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H NMR(DMSO-d₆, 500 MHz): δ 11.24 (br s, 1H), 7.38 (br s, 1H), 7.11 (s, 1H),4.17 (d, J=5.5 Hz, 2H), 1.39 (s, 9H), 1.37 (s, 9H).

Synthesis of 5-(aminomethyl) thiazol-2-amine dihydrochloride (230)

To a stirring solution of compound 229 (300 mg) in CH₂Cl₂ (10 mL) wasadded 4 N HCl in 1, 4-dioxane (5 mL) under argon atmosphere at 0-5° C.;warmed to RT and stirred for 4 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed underreduced pressure. The obtained solid was washed with CH₂Cl₂ (5 mL),EtOAc (5 mL) and dried in vacuo to afford compound 230 (120 mg, HClsalt) as yellow solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR(DMSO-d₆, 500 MHz): δ 9.31 (br s, 1H), 8.53 (br s, 2H), 8.14 (br s, 1H),7.37 (br s, 1H), 7.27 (br s, 1H), 7.17 (br s, 1H), 4.07 (d, J=5.5 Hz,2H).

Synthesis of (2-ethylthiazol-5-yl) methanamine hydrochloride (239)

Synthesis of ethyl 2-chloro-3-oxopropanoate (233)

To a stirring solution of ethyl 2-chloroacetate 231 (5 g, 40.98 mmol)and 232 (3.03 g, 40.98 mmol) in diisopropyl ether (100 mL) under argonatmosphere was added potassium tert-butoxide (5.49 g, 45.08 mmol)portion wise for 10 min at 0° C.; warmed to RT and stirred for 24 h. Thereaction was monitored by TLC; after completion of the reaction, the pHof the reaction mixture was adjusted to ˜6 using 5 N HCl. The obtainedsolid was filtered, washed with diethyl ether (200 mL) and dried invacuo to afford compound 233 (6 g) as pale brown syrup. TLC: 30%EtOAc/hexanes (R_(f): 0.2); LC-MS: 21.49%+75.58%; 149.0 (M⁺-1); (column;X-Select C-18, (50×3.0 mm, 3.5 μm); RT 0.56 min, 0.77 min. 5 MmAq.NH₄OAc:ACN 0.8 mL/min).

Synthesis of ethyl 2-ethylthiazole-5-carboxylate (235)

To a stirring solution of compound 233 (1 g) in ethanol (25 mL) underargon atmosphere were added propanethioamide 234 (594 mg, 6.67 mmol),dry magnesium sulfate (4 g) at RT and heated to reflux for 24 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo, diluted with EtOAc (2×100 mL). Thecombined organic extracts were washed with saturated sodium bicarbonatesolution (2×100 mL), brine (50 mL), dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude was purifiedthrough flash column chromatography using 6% EtOAc/hexanes to affordcompound 235 (330 mg, 27%) as brown syrup. TLC: 10% EtOAc/hexanes(R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.29 (s, 1H), 4.30 (q, J=7.1Hz, 2H), 3.04 (q, J=7.5 Hz, 2H), 1.31 (t, J=7.3 Hz, 3H), 1.29 (t, J=7.3Hz, 3H).

Synthesis of (2-ethylthiazol-5-yl) methanol (236)

To a stirring suspension of lithium aluminium hydride (205 mg, 5.40mmol) in dry THF (15 mL) under inert atmosphere was added compound 235(500 mg, 2.70 mmol) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was cooled to 0° C., quenched with 20% aqueous sodiumhydroxide solution (3 mL), filtered through celite and washed with EtOAc(3×100 mL). The filtrate was dried over sodium sulfate, filtered andconcentrated in vacuo to afford compound 236 (310 mg, 80%) as paleyellow solid. TLC: 50% EtOAc/hexanes (R_(f): 0.4). ¹H-NMR (CDCl₃, 400MHz): δ 7.51 (s, 1H), 4.82 (s, 2H), 3.01 (q, J=7.5 Hz, 2H), 1.38 (t,J=7.6 Hz, 3H).

Synthesis of 5-(chloromethyl)-2-ethylthiazole (237)

To a stirring solution of compound 236 (300 mg, 2.09 mmol) in CH₂Cl₂ (15mL) under inert atmosphere were added triethyl amine (0.6 mL, 4.20mmol), DMAP (25.6 mg, 0.21 mmol) and methanesulfonyl chloride (0.19 mL,2.51 mmol) at 0° C.; warmed to RT and stirred for 2 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with water (50 mL) and extracted with CH₂Cl₂ (3×100 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to afford compound 237 (500 mg, crude) as paleyellow syrup. TLC: 30% EtOAc/hexanes (R_(f): 0.8); LC-MS: 30.71%; 162.0(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.14 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(azidomethyl)-2-ethylthiazole (238)

To a stirring solution of compound 237 (500 mg, 2.26 mmol) in DMF (20mL) under inert atmosphere was added sodium azide (294 mg, 4.52 mmol) atRT and heated to 80° C. for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withice cold water (50 mL) and extracted with EtOAc (3×100 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough flash column chromatography using 15% EtOAc/hexanes to affordcompound 238 (250 mg, 71%) as pale yellow syrup. TLC: 20% EtOAc/hexanes(R_(f): 0.4); ¹H-NMR (CDCl₃, 400 MHz): δ 7.56 (s, 1H), 4.49 (s, 2H),3.03 (q, J=7.6 Hz, 2H), 1.40 (t, J=7.6 Hz, 3H);

Synthesis of (2-ethylthiazol-5-yl) methanamine hydrochloride (239)

To a stirring solution of compound 238 (250 mg, 1.48 mmol) in THF:H₂O(5:1, 12 mL) was added triphenyl phosphine (780 mg, 2.97 mmol) at RT andstirred for 2 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo to obtain the crude.The obtained solid was further dried using toluene (2×5 mL) to obtainthe crude amine.

The above compound was dissolved in CH₂Cl₂ (5 mL) added 4 N HCl in 1,4-dioxane (4 mL) under inert atmosphere at 0° C. and stirred for 30 min.The volatiles were removed in vacuo to obtain the crude, which wastriturated with EtOAc (2 mL), diethyl ether (2 mL) and pentane (5 mL) toafford compound 239 (180 mg, 68%) as an off-white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (DMSO-d₆, 500 MHz): δ 8.48 (br s, 3H),7.74 (s, 1H), 4.25 (q, J=5.5 Hz, 2H), 2.98 (q, J=7.5 Hz, 2H), 1.28 (t,J=7.5 Hz, 3H);

Synthesis of 4-(aminomethyl)-N-methylthiazol-2-amine hydrochloride (242)

Synthesis of tert-butyl ((2-(methylamino) thiazol-4-yl) methyl)carbamate (241)

A mixture of compound 224 (100 mg, 0.41 mmol) and methyl amine 240 (5mL, 33% solution in EtOH) in a sealed tube under argon atmosphere wasadded diisopropyl ethylamine (0.2 mL, 1.21 mmol) under argon atmosphereat RT and heated to 120° C. for 16 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The crude was purified through silica gel column chromatography using70% EtOAc/hexanes to afford compound 241 (90 mg, 92%) as colorlesssticky solid. TLC: 50% EtOAc/hexanes (R_(f). 0.2); ¹H NMR (DMSO-d₆, 400MHz): δ 7.26 (d, J=5.6 Hz, 2H), 6.77 (s, 1H), 4.05 (d, J=5.7 Hz, 2H),2.76 (d, J=4.8 Hz, 3H), 1.38 (s, 9H).

Synthesis of 4-(aminomethyl)-N-methylthiazol-2-amine hydrochloride (242)

To a stirring solution of compound 241 (90 mg, 0.37 mmol) in CH₂Cl₂ (3mL) under argon atmosphere was added 4 N HCl in 1, 4-dioxane (3 mL) at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was titurated with diethyl ether (5 mL) and dried invacuo to afford compound 242 (70 mg, HCl salt) as brown solid. TLC: 30%EtOAc/hexanes (R_(f): 0.1); ¹H NMR (DMSO-d₆, 400 MHz): δ 9.73-9.27 (m,1H), 8.39 (br s, 3H), 7.35 (s, 1H), 4.08 (q, J=5.3 Hz, 2H), 2.95 (s,3H).

Synthesis of 4-(aminomethyl)-N,N-dimethylthiazol-2-amine hydrochloride(245)

Synthesis of tert-butyl ((2-(dimethylamino) thiazol-4-yl) methyl)carbamate (244)

To a stirring solution of compound 224 (100 mg, 0.41 mmol) in CH₃CN (3mL) under argon atmosphere were added dimethyl amine hydrochloride 243(648 mg, 8.06 mmol) and diisopropyl ethylamine (0.2 mL, 1.21 mmol) in asealed tube at RT and heated to 120° C. for 54 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with EtOAc (2×50 mL) washed with water (20 mL). The organicextract was dried over sodium sulphate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 20% EtOAc/hexanes to afford compound 244 (80mg, 77%) as an off-white solid. TLC: 30% EtOAc/hexanes (R_(f): 0.2); ¹HNMR (DMSO-d₆, 400 MHz): δ 7.29 (t, J=4.8 Hz, 1H), 6.89 (s, 1H), 4.08 (d,J=5.9 Hz, 2H), 2.97 (s, 6H), 1.38 (s, 9H).

Synthesis of 4-(aminomethyl)-N, N-dimethylthiazol-2-amine hydrochloride(245)

To a stirring solution of compound 244 (100 mg, 0.38 mmol) in CH₂Cl₂ (3mL) under argon atmosphere was added 4 N HCl in 1, 4-dioxane (3 mL) at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was titurated with diethyl ether (5 mL) and dried invacuo to afford compound 245 (75 mg, HCl salt) as an off-white solid.TLC: 50% EtOAc/hexanes (R₁. 0.1); ¹H NMR (DMSO-d₆, 400 MHz): δ 8.44 (brs, 3H), 7.38 (s, 1H), 4.10 (q, J=5.6 Hz, 2H), 3.14 (s, 6H).

Synthesis of (2-isopropylthiazol-5-yl) methanamine hydrochloride (251)

Synthesis of ethyl 2-isopropylthiazole-5-carboxylate (247)

To a stirring solution of compound 233 (3.05 g) in ethanol (60 mL) underargon atmosphere were added 2-methylpropanethioamide 246 (1.5 g, 14.56mmol), dry magnesium sulfate (5 g) at RT and heated to reflux for 24 h.The reaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The residue was diluted with saturatedsodium bicarbonate solution (100 mL), extracted with EtOAc (3×100 mL).The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude was purifiedthrough flash column chromatography using 2% EtOAc/hexanes to affordcompound 247 (550 mg, 17%) as brown syrup. TLC: 10% EtOAc/hexanes(R_(f): 0.5); ¹H NMR (500 MHz, DMSO-d₆) δ 8.31 (s, 1H), 4.30 (q, J=7.0Hz, 2H), 3.36-3.29 (m, 1H), 1.34 (d, J=6.9 Hz, 6H), 1.29 (t, J=7.1 Hz,3H).

Synthesis of (2-isopropylthiazol-5-yl) methanol (248)

To a stirring solution of compound 247 (550 mg, 2.76 mmol) in dry THF(10 mL) under inert atmosphere was added lithium aluminium hydride (210mg, 5.52 mmol) at 0° C.; warmed to RT and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was cooled to 0° C., quenched with 15% aqueous sodium hydroxidesolution (3 mL), filtered through celite and washed with EtOAc (100 mL).The filtrate was dried over sodium sulfate, filtered and concentrated invacuo to afford compound 248 (360 mg, 83%) as pale yellow syrup. TLC:50% EtOAc/hexanes (R_(f): 0.3). ¹H NMR (400 MHz, DMSO-d₆) δ 7.47 (s,1H), 5.43 (t, J=5.7 Hz, 1H), 4.61 (dd, J=5.6, 0.6 Hz, 2H), 3.26-3.19 (m,1H), 1.30 (d, J=6.9 Hz, 6H).

Synthesis of 5-(chloromethyl)-2-isopropylthiazole (249)

To a stirring solution of compound 248 (350 mg, 2.23 mmol) in CH₂Cl₂ (20mL) under inert atmosphere were added triethyl amine (0.64 mL, 4.45mmol), DMAP (27.2 mg, 0.22 mmol) and methanesulfonyl chloride (0.2 mL,2.67 mmol) at 0° C.; warmed to RT and stirred for 3 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with water (50 mL) and extracted with CH₂Cl₂ (2×100 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to afford compound 249 (500 mg, crude) as paleyellow syrup. TLC: 40% EtOAc/hexanes (R_(f): 0.8); LC-MS: 70.54%; 175.8(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.34 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(azidomethyl)-2-isopropylthiazole (250)

To a stirring solution of compound 249 (500 mg, 2.26 mmol) in DMF (20mL) under inert atmosphere was added sodium azide (445 mg, 6.85 mmol) atRT and heated to 80° C. for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withice cold water (100 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough column chromatography using 8% EtOAc/hexanes to afford compound250 (255 mg, 63%) as colorless liquid. TLC: 10% EtOAc/hexanes (R_(f):0.4); ¹H NMR (500 MHz, DMSO-d₆): δ=7.67 (s, 1H), 4.69 (s, 2H), 3.29-3.24(m, 1H), 1.32 (d, J=6.9 Hz, 8H).

Synthesis of (2-isopropylthiazol-5-yl) methanamine hydrochloride (251)

To a stirring solution of compound 250 (250 mg, 1.37 mmol) in THF:H₂O(5:1, 12 mL) was added triphenyl phosphine (720 mg, 2.74 mmol) at RT andstirred for 2 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo to obtain the crude.The obtained solid was further dried using toluene (2×5 mL) to obtainthe crude amine.

The above crude compound was dissolved in CH₂Cl₂ (5 mL) added 4 N HCl in1, 4-dioxane (10 mL) under inert atmosphere at 0° C. and stirred for 30min. The volatiles were removed in vacuo to obtain the crude, which wastriturated with EtOAc (2 mL), diethyl ether (2 mL) and pentane (5 mL) toafford compound 251 (170 mg, 65%) as low melting hygroscopic solid. TLC:5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (500 MHz, DMSO-d₆): δ 8.29 (br s,2H), 7.72 (s, 1H), 4.25 (d, J=5.8 Hz, 2H), 3.29-3.24 (m, 1H), 1.30 (d,J=6.9 Hz, 6H)

Synthesis of (2-(trifluoromethyl) thiazol-5-yl) methanamine (255)

Synthesis of (2-(trifluoromethyl) thiazol-5-yl) methanol (253)

To a stirring solution of ethyl 2-(trifluoromethyl)thiazole-5-carboxylate 252 (500 mg, 2.22 mmol) in THF (25 mL) underinert atmosphere was added lithium aluminium hydride (126 mg, 3.33 mmol)at 0° C.; warmed to RT and stirred for 3 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wascooled to 0° C., quenched with ice-cold water (5 mL), followed by 10%aqueous sodium hydroxide solution (3 mL), filtered through celite andwashed with THF (10 mL). The filtrate was dried over sodium sulfate,filtered and concentrated in vacuo to afford compound 253 (300 mg, 73%)as pale yellow liquid. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.98 (s, 1H), 5.90(t, J=5.7 Hz, 2H), 4.79 (d, J=5.6 Hz, 3H).

Synthesis of (2-(trifluoromethyl) thiazol-5-yl) methyl methanesulfonate(254)

To a stirring solution of compound 253 (200 mg, 1.09 mmol) in CH₂Cl₂ (10mL) under inert atmosphere were added triethyl amine (0.47 mL, 3.27mmol), methanesulfonyl chloride (0.16 mL, 2.18 mmol) at 0° C.; warmed toRT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with CH₂Cl₂(100 mL), washed with 10% NaHCO₃ solution (50 mL). The organic extractwas dried over sodium sulfate, filtered and concentrated in vacuo toafford crude compound 254 (200 mg) as yellow liquid. TLC: 40%EtOAc/hexanes (R_(f): 0.2); LC-MS: 24.48%; 261.8 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.29 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(trifluoromethyl) thiazol-5-yl) methanamine (255)

To a stirring solution of compound 254 (200 mg, crude) in EtOH (10 mL)was added aqueous ammonia (10 mL) at 0° C.; heated to 100° C. andstirred for 16 h in a sealed tube. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 10% MeOH/CH₂Cl₂ to afford compound 255 (56 mg) aspale yellow sticky solid. 41 NMR (DMSO-d₆, 400 MHz): δ 7.92 (s, 1H),6.80 (br s, 2H), 4.01 (s, 2H).

Synthesis of (4-(trifluoromethyl) thiazol-5-yl) methanamine (263)

Synthesis of ethyl 2-chloro-4, 4, 4-trifluoro-3-oxobutanoate (257)

To a stirring solution of ethyl 4, 4, 4-trifluoro-3-oxobutanoate 256 (10g, 54.2 mmol) in CH₂Cl₂ (25 mL) under inert atmosphere was addedsulfuryl chloride (5.2 mL, 65.0 mmol) at 0° C.; warmed to RT and stirredfor 16 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo at RT to afford compound257 (5 g) as yellow liquid. TLC: 10% EtOAc/hexanes (R_(f): 0.5). ¹H NMR(CDCl₃, 400 MHz): δ 5.62 (s, 1H), 4.29 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2Hz, 3H).

Synthesis of ethyl 2-amino-4-(trifluoromethyl) thiazole-5-carboxylate(259)

To a stirring solution of compound 257 (5 g, crude) in ethanol (25 mL)under inert atmosphere was added thiourea 258 (3.3 g, 45.8 mmol) at RTand heated to reflux for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. Theresidue was diluted with diethyl ether (200 mL) and washed with water(100 mL). The organic extract was dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 10-15% EtOAc/hexanes toafford compound 259 (2.7 g, 49%) as pale yellow solid. TLC: 30%EtOAc/hexanes (R_(f): 0.5); ¹H NMR (DMSO-d₆, 400 MHz): δ 8.21 (s, 2H),4.21 (q, J=7.0 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H).

Synthesis of ethyl 4-(trifluoromethyl) thiazole-5-carboxylate (260)

To a stirring solution of compound 259 (2.7 g, 11.25 mmol) in DMF (10mL) under inert atmosphere was added tert-butyl nitrate (5.8 g, 56.25mmol) at 0° C.; heated to 100° C. and stirred for 4 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with diethyl ether (2×100 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toafford the crude. The crude was purified through silica gel columnchromatography using 5-10% EtOAc/hexanes to afford compound 260 (1.5 g,60%) as pale yellow solid. TLC: 20% EtOAc/hexanes (R_(f): 0.7); ¹H NMR(DMSO-d₆, 400 MHz): 9.41 (s, 1H), 4.35 (q, J=7.0 Hz, 2H), 1.32 (t, J=7.1Hz, 3H).

Synthesis of (4-(trifluoromethyl) thiazol-5-yl) methanol (261)

To a stirring solution of compound 260 (500 mg, 2.22 mmol) in THF (20mL) under inert atmosphere was added lithium aluminium hydride (169 mg,4.44 mmol) portion wise at 0° C.; warmed to RT and stirred for 6 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was cooled to 0° C., quenched with ice-cold water (1mL), followed by 15% aqueous sodium hydroxide solution (1.5 mL),filtered through celite and washed with THF (10 mL). The filtrate wasdried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 30% EtOAc/hexanes to afford compound 261 (205 mg,50%) as colorless liquid. ¹H NMR (DMSO-d₆, 400 MHz): δ 9.12 (s, 1H),6.15 (t, J=5.6 Hz, 1H), 4.85-4.83 (m, 2H).

Synthesis of (4-(trifluoromethyl) thiazol-5-yl) methyl methanesulfonate(262)

To a stirring solution of compound 261 (200 mg, 1.09 mmol) in CH₂Cl₂ (10mL) under inert atmosphere were added triethyl amine (0.47 mL, 3.27mmol), methanesulfonyl chloride (0.23 mL, 2.73 mmol) at 0° C.; warmed toRT and stirred for 6 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with CH₂Cl₂(2×50 mL), washed with water (100 mL). The organic extract was driedover sodium sulfate, filtered and concentrated in vacuo to affordcompound 262 (210 mg) as yellow liquid. TLC: 30% EtOAc/hexanes (R_(f):0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ 9.29 (s, 1H), 5.64 (s, 2H), 3.34 (s,3H).

Synthesis of (4-(trifluoromethyl) thiazol-5-yl) methanamine (263)

To a stirring solution of compound 262 (200 mg, 0.76 mmol) in EtOH (10mL) was added aqueous ammonia (10 mL) at 0° C.; warmed to RT and stirredfor 16 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 10%MeOH/CH₂Cl₂ to afford compound 263 (85 mg, 61%) as pale yellow stickysolid. ¹H NMR (DMSO-d₆, 400 MHz): 9.21 (s, 1H), 7.27 (br s, 2H), 4.32(s, 2H).

Synthesis of 2-(thiazol-5-yl) propan-2-amine hydrochloride (270)

Synthesis of N-methoxy-N-methylthiazole-5-carboxamide (266)

To a stirring solution of thiazole-5-carboxylic acid 264 (2 g, 15.44mmol) in CH₂Cl₂ (40 mL) under inert atmosphere were added EDCI.HCl (3.26g, 17.04 mmol), HOBt (1 g, 7.74 mmol), N,O-dimethyl hydroxylaminehydrochloride 265 (1.81 g, 18.59 mmol) and diisopropylethylamine (13.4mL, 77.45 mmol) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (70 mL) and extracted withCH₂Cl₂ (3×70 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel flash column chromatography using30-40% EtOAc/hexanes to afford compound 266 (1.6 g, 60%) as white solid.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.6); ¹H NMR (DMSO-d₆, 400 MHz): 9.32 (s,1H), 8.52 (s, 1H), 3.77 (s, 3H), 3.30 (s, 3H).

Synthesis of 1-(thiazol-5-yl) ethan-1-one (267)

To a stirring solution of compound 266 (1.6 g, 9.30 mmol) in dry THF (20mL) under inert atmosphere was added methyl magnesium bromide (4.65 mL,13.95 mmol, 3 M solution in Et₂O) dropwise for 10 min at −10° C.; warmedto RT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withsaturated ammonium chloride (30 mL) and extracted with EtOAc (2×60 mL).The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel flash column chromatography using 25-30%EtOAc/hexanes to afford compound 267 (1 g, 85%) as white solid. TLC: 50%EtOAc/hexanes (R_(f): 0.8); ¹H NMR (DMSO-d₆, 400 MHz): δ 9.40 (s, 1H),8.71 (s, 1H), 2.60 (s, 3H).

Synthesis of 2-methyl-N-(1-(thiazol-5-yl) ethylidene)propane-2-sulfinamide (269)

To a stirring solution of compound 267 (500 mg, 3.93 mmol) in THF (20mL) under inert atmosphere was added 2-methylpropane-2-sulfinamide 268(570 mg, 4.70 mmol) and titanium (IV) isopropoxide (2.23 g, 7.87 mmol)at RT and heated to reflux and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted diethyl ether (300 mL) and water (10 mL) and stirred for 10min. The organic extract was dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel flash column chromatography using 35-40%EtOAc/hexanes to afford compound 269 (600 mg, 66%) as brown syrup. TLC:40% EtOAc/hexanes (R_(f): 0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ 9.29 (s,1H), 8.58 (s, 1H), 2.75 (s, 3H), 1.15 (s, 9H).

Synthesis of 2-methyl-N-(2-(thiazol-5-yl) propan-2-yl)propane-2-sulfinamide (270)

To a stirring solution of compound 269 (300 mg, 1.30 mmol) in Toluene(10 mL) under inert atmosphere was added methyl magnesium bromide (2.6mL, 7.82 mmol, 3 M solution in Et₂O) dropwise for 10 min at −70° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was quenched withsaturated ammonium chloride (30 mL) and extracted with EtOAc (2×60 mL).The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel flash column chromatography using 60-70%EtOAc/hexanes to afford compound 270 (140 mg, 44%) as yellow syrup. TLC:5% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ 8.99 (s, 1H),7.81 (s, 1H), 5.54 (s, ¹H), 1.68 (s, 3H), 1.61 (s, 3H), 1.32 (s, 9H).

Synthesis of 2-(thiazol-5-yl) propan-2-amine hydrochloride (271)

To a stirring solution of compound 270 (100 mg, 0.40 mmol) in MeOH (4mL) under inert atmosphere was added 2 M HCl in diethyl ether (4 mL) at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude which was washed with diethyl ether (2×10 mL)to afford compound 271 (65 mg, 90%) as an off-white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H NMR (DMSO-d₆, 400 MHz): δ 9.11 (s, 1H),8.99 (br s, 3H), 8.04 (s, 1H), 1.78 (s, 6H).

Synthesis of (2-(tert-butyl) thiazol-5-yl) methanamine hydrochloride(277)

Synthesis of ethyl 2-(tert-butyl) thiazole-5-carboxylate (273)

To a stirring solution of compound 233 (11.2 g, 74.66 mmol) in ethanol(100 mL) under argon atmosphere were added 2, 2-dimethylpropanethioamide272 (8.73 g, 74.66 mmol) and dry magnesium sulfate (20 g) at RT andheated to reflux for 24 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo, dilutedwith water (200 mL) and extracted with EtOAc (2×200 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 2-15% EtOAc/hexanes toafford compound 273 (3.7 g, 23%) as pale yellow syrup. TLC: 20%EtOAc/hexanes (R_(f): 0.6); ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.29 (s, 1H),4.28 (q, J=7.2 Hz, 2H), 1.38 (s, 9H), 1.27 (t, J=7.1 Hz, 3H).

Synthesis of (2-(tert-butyl) thiazol-5-yl) methanol (274)

To a stirring solution of compound 273 (3.7 g, 20.10 mmol) in dry THF(50 mL) under inert atmosphere was added lithium aluminium hydride (1.5g, 40.21 mmol) portion wise for 10 min at 0° C.; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was cooled to 0° C., quenched withice cold water (100 mL), filtered through celite and washed with EtOAc(2×100 mL). The filtrate was removed in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 5-20%EtOAc/hexanes to afford compound 274 (1.7 g, 50%) as pale yellow thicksyrup. TLC: 30% EtOAc/hexanes (R_(f): 0.4). ¹H-NMR (DMSO-d₆, 500 MHz): δ7.46 (s, 1H), 5.42 (t, J=5.6 Hz, 1H), 4.60 (d, J=5.5 Hz, 2H), 1.34 (s,9H).

Synthesis of 2-(tert-butyl)-5-(chloromethyl) thiazole (275)

To a stirring solution of compound 274 (1.7 g, 13.17 mmol) in CH₂Cl₂ (50mL) under inert atmosphere were added triethyl amine (2.3 mL, 19.76mmol) and methanesulfonyl chloride (1.30 mL, 15.81 mmol) at 0° C.;warmed to RT and stirred for 4 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was quenched withsaturated sodium carbonate (100 mL) and extracted with CH₂Cl₂ (2×100mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to afford compound 275 (2.5 g, crude)as colorless syrup. TLC: 30% EtOAc/hexanes (R_(f): 0.8); LC-MS: 61.93%;190.2 (M⁺+1); (column; X-select C18, (50×3.0 mm, 2.5 μm); RT 4.43 min.2.5 mM Aq. NH₄OAc:ACN: 0.8 mL/min).

Synthesis of 5-(azidomethyl)-2-(tert-butyl) thiazole (276)

To a stirring solution of compound 275 (2.5 g, crude) in DMF (25 mL)under inert atmosphere was added sodium azide (1.71 g, 26.45 mmol) at RTand heated to 80° C. for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with icecold water (50 mL) and extracted with EtOAc (2×100 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 5-10% EtOAc/hexanes toafford compound 276 (1 g, 38%) as colorless syrup. TLC: 20%EtOAc/hexanes (R_(f): 0.5); ¹H-NMR (DMSO-d₆, 500 MHz): 7.66 (s, 1H),4.69 (s, 2H), 1.37 (s, 9H).

Synthesis of (2-(tert-butyl) thiazol-5-yl) methanamine hydrochloride(277)

To a stirring solution of compound 276 (1 g, 5.10 mmol) in THF:H₂O (4:1,20 mL) was added triphenyl phosphine (2.67 g, 10.20 mmol) at 0° C.portion wise for 15 min; warmed to RT and stirred for 2 h. The reactionwas monitored by TLC; after completion of the reaction, the volatileswere removed in vacuo to obtain the crude. The obtained solid wasfurther dried using toluene (2×5 mL) to obtain the crude amine.

The above compound (600 mg, crude) was dissolved in CH₂Cl₂ (5 mL) underinert atmosphere was added 4 N HCl in 1, 4-dioxane (10 mL) at 0° C.;warmed to RT and stirred for 3 h. The volatiles were removed in vacuo toobtain the crude. The crude was washed with CH₂Cl₂ (10 mL), diethylether (10 mL) and dried in vacuo to afford compound 277 (700 mg, 96%) asan off-white solid. TLC: 20% EtOAc/hexanes (R_(f): 0.2); 41 NMR(DMSO-d₆, 500 MHz): δ 8.49 (br s, 3H), 7.75 (s, 1H), 4.25 (q, J=5.6 Hz,2H), 1.37 (s, 9H).

Synthesis of 5-(aminomethyl) thiazole-2-carbonitrile (282)

Synthesis of 5-methylthiazole-2-carbonitrile (279)

To a stirring solution of 5-methylthiazol-2-amine 278 (10 g, 87.71 mmol)in CH₃CN (100 mL) under argon atmosphere were added tert-butyl nitrite(18 g, 17.54 mmol), copper (I) cyanide (23.6 g, 263.51 mmol) at RT;heated to reflux and stirred for 2 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo toobtain the crude, which was purified through silica gel columnchromatography using 20% EtOAc/hexanes to afford compound 279 (2 g, 20%)as white solid. TLC: 30% EtOAc/hexanes (R_(f): 0.3); ¹H-NMR (DMSO-d₆,400 MHz): δ 7.98 (s, 1H), 2.59 (s, 3H).

Synthesis of 5-(bromomethyl) thiazole-2-carbonitrile (280)

To a stirring solution of compound 279 (2.4 g, 19.35 mmol) in CCl₄ (50mL) under argon atmosphere was added N-bromosuccinimide (3.4 g, 19.35mmol), azobisisobutyronitrile (317 mg, 1.93 mmol) at RT; heated toreflux and stirred for 8 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 15% EtOAc/hexanes to afford compound 280 (2 g, 51%)as yellow solid. TLC: 10% EtOAc/hexanes (R_(f): 0.5); ¹H-NMR (DMSO-d₆,400 MHz): δ 8.26 (s, 1H), 5.14 (s, 2H).

Synthesis of 5-(azidomethyl) thiazole-2-carbonitrile (281)

To a stirring solution of compound 280 (2 g, 9.85 mmol) in DMF (25 mL)under inert atmosphere was added sodium azide (1.9 g, 29.55 mmol) at 0°C.; warmed to RT and stirred for 2 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withice cold water (50 mL) and extracted with EtOAc (3×100 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 30% EtOAc/hexanes toafford compound 281 (1 g, 62%) as yellow syrup. TLC: 30% EtOAc/hexanes(R_(f): 0.4); ¹H-NMR (DMSO-d₆, 500 MHz): δ 7.95 (s, 1H), 4.95 (s, 2H).

Synthesis of 5-(aminomethyl) thiazole-2-carbonitrile (282)

To a stirring solution of compound 281 (1 g, 6.06 mmol) in THF:H₂O (3:1,20 mL) was added triphenyl phosphine (3.1 g, 12.12 mmol) at 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo toobtain the crude, The crude was purified through silica gel columnchromatography using 50% EtOAc/hexanes to afford compound 282 (1 g, 62%)as yellow syrup. TLC: 80% EtOAc/hexanes (R_(f): 0.4); ¹H-NMR (DMSO-d₆,400 MHz): δ 8.01 (s, 1H), 4.04 (s, 2H).

Synthesis of (2-(4-fluorophenyl) thiazol-5-yl) methanamine hydrochloride(285)

Synthesis of tert-butyl ((2-(4-fluorophenyl) thiazol-5-yl) methyl)carbamate (284)

To a stirring solution of compound 224 (500 mg, 2.01 mmol) in2-methyltetrahydrofuran (50 mL) under argon atmosphere were added(4-fluorophenyl) boronic acid 283 (309 mg, 2.25 mmol), sodium carbonate(535 mg, 5.05 mmol) at RT and purged under argon atmosphere for 10 min.To this was added Pd(dppf)Cl₂ (73.5 mg, 0.10 mmol); heated to 110° C.and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 40% EtOAc/hexanes to afford compound 284 (160 mg,25%) as yellow solid. TLC: 40% EtOAc/hexanes (R_(f): 0.4); ¹H-NMR(DMSO-d₆, 400 MHz): δ 7.94 (dd, J=8.7, 5.5 Hz, 2H), 7.68 (s, 1H), 7.56(t, J=4.9 Hz, 1H), 7.32 (t, J=8.7 Hz, 2H), 4.33 (d, J=5.8 Hz, 2H), 1.40(s, 9H).

Synthesis of (2-(4-fluorophenyl) thiazol-5-yl) methanamine hydrochloride(285)

To a stirring solution of compound 284 (160 mg, 0.51 mmol) in CH₂Cl₂ (5mL) was added 4 N HCl in 1, 4-dioxane (2 mL) under argon atmosphere at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to afford compound 285 (100 mg, 94%) as pink solid. TLC: 40%EtOAc/hexanes (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.55 (br s,3H), 8.01-7.96 (m, 3H), 7.36 (t, J=8.8 Hz, 2H), 4.34 (q, J=5.7 Hz, 2H).

Synthesis of 2-((5-(aminomethyl) thiazol-2-yl) thio)-N,N-dimethylethan-1-amine hydrochloride (288)

Synthesis of tert-butyl ((2-((2-(dimethylamino) ethyl) thio)thiazol-5-yl) methyl) carbamate (287)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (1 g, 4.03 mmol) in DMF (20 mL) under inert atmosphere wasadded 2-(dimethylamino) ethane-1-thiol hydrochloride 286 (1.1 g, 8.06mmol) and cesium carbonate (4 g, 12.09 mmol) at RT in a sealed tube;heated to 100° C. and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was pouredinto ice-cold water (20 mL) and extracted with EtOAc (2×50 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to afford compound 287 (1.1 g, 87%) as brownsyrup. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ7.46 (s, 1H), 4.22 (d, J=5.5 Hz, 2H), 3.28 (t, J=7.1 Hz, 2H), 2.56 (t,J=7.1 Hz, 2H), 2.16 (s, 6H), 1.38 (s, 9H).

Synthesis of 2-((5-(aminomethyl) thiazol-2-yl) thio)-N,N-dimethylethan-1-amine hydrochloride (288)

To a stirring solution of compound 287 (1.1 g, 3.47 mmol) in CH₂Cl₂ (5mL) was added 4 N HCl in 1, 4-dioxane (10 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was washed with diethyl ether (2×10 mL), n-pentane(2×10 mL) and dried in vacuo to afford compound 288 (700 mg, HCl salt)as an off-white solid. TLC: 30% 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR(DMSO-d₆, 500 MHz): δ 8.67 (br s, 3H), 7.83 (s, 1H), 4.23 (q, J=4.9 Hz,2H), 3.63-3.57 (m, 2H), 3.41-3.34 (m, 2H), 2.77 (d, J=4.6 Hz, 6H).

Synthesis of (2-phenylthiazol-5-yl) methanamine hydrochloride (291)

Synthesis of tert-butyl ((2-phenylthiazol-5-yl) methyl) carbamate (290)

To a stirring solution of compound 224 (250 mg, 1.00 mmol) in2-methyltetrahydrofuran (10 mL) under argon atmosphere were addedphenylboronic acid 289 (136 mg, 1.10 mmol), sodium carbonate (265 mg,2.50 mmol) at RT and purged under argon atmosphere for 20 min. To thiswas added Pd(dppf)Cl₂ (36.5 mg, 0.05 mmol) at RT; heated to 110° C. andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using20% EtOAc/hexanes to afford compound 290 (110 mg, 37%) as an off-whitesolid. TLC: 30% EtOAc/hexanes (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 500 MHz): δ7.89 (d, J=6.4 Hz, 2H), 7.69 (s, 1H), 7.56 (t, J=6.4 Hz, 1H), 7.51-7.46(m, 3H), 4.34 (d, J=5.8 Hz, 2H), 1.40 (s, 9H).

Synthesis of (2-phenylthiazol-5-yl) methanamine hydrochloride (291)

To a stirring solution of compound 290 (1.6 g, 5.51 mmol) in CH₂Cl₂ (25mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (10 mL) at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was washed with diethyl ether (2×5mL) and dried in vacuo to afford compound 291 (1 g, 83%) as an off-whitesolid. TLC: 30% EtOAc/hexanes (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ8.25 (br s, 2H), 7.98 (s, 1H), 7.94-7.92 (m, 2H), 7.54-7.51 (m, 3H),4.35 (q, J=6.0 Hz, 2H).

Synthesis of (2-methylthiazol-5-yl) methanamine hydrochloride (297)

Synthesis of ethyl 2-methylthiazole-5-carboxylate (293)

To a stirring solution of ethyl 2-chloro-3-oxopropanoate 233 (26 g,173.33 mmol) in ethanol (200 mL) under argon atmosphere were addedethanethioamide 292 (10 g, 133.33 mmol), dry magnesium sulfate (10 g) atRT and heated to reflux for 24 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo,diluted with EtOAc (500 mL). The combined organic extracts were washedwith saturated sodium bicarbonate solution (2×200 mL), brine (200 mL),dried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through flash column chromatographyusing 6% EtOAc/hexanes to afford compound 293 (8 g, 35%) as brown syrup.TLC: 25% EtOAc/hexanes (R_(f): 0.7); ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.24(s, 1H), 4.27 (q, J=7.2 Hz, 2H), 2.70 (s, 3H), 1.27 (t, J=7.1 Hz, 3H).

Synthesis of (2-methylthiazol-5-yl) methanol (294)

To a stirring suspension of lithium aluminium hydride (3.1 g, 93.56mmol) in dry THF (10 mL) under inert atmosphere was added compound 293(8 g, 46.78 mmol) in dry THF (50 mL) dropwise for 15 min at 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was cooled to 0°C., quenched with 15% aqueous sodium hydroxide solution (10 mL),filtered through celite and washed with EtOAc (3×100 mL). The filtratewas dried over sodium sulfate, filtered and concentrated in vacuo toafford compound 294 (5 g, 83%) as an off-white solid. TLC: 50%EtOAc/hexanes (R_(f): 0.3). LC-MS: 97.32%; 130.22 (M⁺+1); (column;X-select CSH C18, (50×3.0 mm, 2.5 μm); RT 0.65 min. 2.5 mM Aq.NH₄OAc:ACN: 0.8 mL/min).

Synthesis of 5-(chloromethyl)-2-methylthiazole (295)

To a stirring solution of compound 294 (5 g, 38.75 mmol) in CH₂Cl₂ (150mL) under inert atmosphere were added triethyl amine (8.3 mL, 58.13mmol), methanesulfonyl chloride (4.6 mL, 46.51 mmol) at 0° C.; warmed toRT and stirred for 4 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(50 mL) and extracted with CH₂Cl₂ (2×100 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to afford compound 295 (5 g, 87%) as pale yellow syrup. TLC: 30%EtOAc/hexanes (R_(f): 0.8); LC-MS: 77.92%; 147.7 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.71 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(azidomethyl)-2-methylthiazole (296)

To a stirring solution of compound 295 (5 g, 34.01 mmol) in DMF (100 mL)under inert atmosphere was added sodium azide (2.21 g, 34.01 mmol) at RTand heated to 80° C. for 6 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with icecold water (50 mL) and extracted with EtOAc (3×100 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 10% EtOAc/hexanes toafford compound 296 (2.3 g, 44%) as off-white thick syrup. TLC: 20%EtOAc/hexanes (R_(f): 0.5); ¹H-NMR (DMSO-d₆, 500 MHz): δ 7.64 (s, 1H),4.67 (s, 2H), 2.65 (s, 3H).

Synthesis of (2-methylthiazol-5-yl) methanamine hydrochloride (297)

To a stirring solution of compound 296 (2.3 g, 14.93 mmol) in THF:H₂O(5:1, 80 mL) was added triphenyl phosphine (7.8 g, 29.87 mmol) at 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo toobtain the crude, which was triturated with diethyl ether (20 mL) toafford amine (900 mg, 47%) as colorless syrup. TLC: 10% MeOH/CH₂Cl₂(R_(f): 2);

The above compound was dissolved in CH₂Cl₂ (10 mL) added 4 N HCl in 1,4-dioxane (5 mL) under inert atmosphere at 0° C.; warmed to RT andstirred for 3 h. The volatiles were removed in vacuo to obtain thecrude, which was triturated with EtOAc (2 mL), diethyl ether (2 mL) toafford compound 297 (1.1 g, 95%) as an off-white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (DMSO-d₆, 500 MHz): δ 8.59 (br. s, 3H),7.74 (s, 1H), 4.23 (q, J=5.6 Hz, 2H), 2.66 (s, 3H)

Synthesis of (4′-fluoro-[1,1′-biphenyl]-3-yl) methanamine hydrochloride(301)

Synthesis of tert-butyl (3-bromobenzyl) carbamate (299)

To a stirring solution of (3-bromophenyl) methanamine 298 (5 g, 26.88mmol) in CH₂Cl₂ (50 mL) under argon atmosphere were added triethylamine(1.16 mL, 80.59 mmol), Boc-anhydride (5.8 mL, 26.88 mmol) at 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (100 mL) and extracted with CH₂Cl₂ (2×100 mL). The combinedorganic extracts were washed with water (25 mL), dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 5%EtOAc/hexanes to afford compound 299 (5 g, 65%) as white solid. TLC: 10%EtOAc/hexanes (R_(f): 0.6); ¹H-NMR (DMSO-d₆, 400 MHz): δ 7.45-7.37 (m,3H), 7.32-7.20 (m, 2H), 4.12 (d, J=6.1 Hz, 2H), 1.39 (s, 9H).

Synthesis of tert-butyl ((4′-fluoro-[1, 1′-biphenyl]-3-yl) methyl)carbamate (300)

To a stirring solution of tert-butyl (3-bromobenzyl) carbamate 299 (100mg, 0.34 mmol) in a mixture of toluene:EtOH (4:1, 2.5 mL) under inertatmosphere were added 2 M aqueous sodium carbonate solution (0.5 mL) and(4-fluorophenyl) boronic acid 283 (58 mg, 0.41 mmol) and at RT andpurged under argon atmosphere for 15 min. To this was added Pd(dppf)Cl₂(7.6 mg, 0.01 mmol) and heated to 80° C. for 6 h. The reaction wasmonitored by TLC; after completion of the reaction, the organic layerwas separated dried over sodium sulphate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 2-8% EtOAc/hexanes to afford compound 300(100 mg, 95%) as an off-white solid. TLC: 10% EtOAc/hexanes (R_(f):0.3); ¹H-NMR (DMSO-d₆, 400 MHz): 7.67 (dd, J=8.7, 5.4 Hz, 2H), 7.52-7.48(m, 2H), 7.40 (t, J=7.7 Hz, 2H), 7.29 (t, J=8.8 Hz, 2H), 7.23 (d, J=7.3Hz, 1H), 4.19 (d, J=6.0 Hz, 2H), 1.40 (s, 9H).

Synthesis of (4′-fluoro-[1, r-biphenyl]-3-yl) methanamine hydrochloride(301)

To a stirring solution of compound 300 (130 mg, 0.43 mmol) in CH₂Cl₂ (2mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (2 mL) at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to afford compound 301 (90 mg, 88%) as an off-white solid. TLC:30% EtOAc/hexanes (R_(f): 0.1); LC-MS: 98.27%; 201.9 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.76 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-morpholinothiazol-5-yl) methanamine hydrochloride (389)

Synthesis of tert-butyl ((2-morpholinothiazol-5-yl) methyl) carbamate(303)

A stirred solution of compound 224 (300 mg, 1.21 mmol) in morpholine 302(3 mL) under argon atmosphere was heated to 100° C. and stirred for 6 h.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (20 mL) and extracted with EtOAc(2×100 mL). The combined organic extracts were washed with water (50 mL)and brine (50 mL), dried over sodium sulphate, filtered and concentratedin vacuo to afford compound 303 (250 mg, 69%) as a colorless semi solid.TLC: 30% EtOAc/hexanes (R_(f): 0.3); ¹H-NMR (DMSO-d₆, 400 MHz): 7.31 (t,J=5.1 Hz, 1H), 6.94 (s, 1H), 4.09 (d, J=5.8 Hz, 2H), 3.70-3.62 (m, 4H),3.29-3.27 (m, 4H), 1.36 (s, 9H).

Synthesis of (2-morpholinothiazol-5-yl) methanamine hydrochloride (304)

To a stirring solution of compound 303 (250 mg, 0.83 mmol) in CH₂Cl₂ (20mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (10 mL) at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was washed with diethyl ether (2×5mL) and dried in vacuo to afford compound 304 (200 mg, HCl salt) as anoff-white solid. TLC: 30% EtOAc/hexanes (R_(f): 0.1); ¹H-NMR (DMSO-d₆,500 MHz): δ 8.36 (br s, 3H), 7.31 (s, 1H), 4.11 (q, J=5.4 Hz, 2H),3.75-3.67 (m, 4H), 3.45-3.37 (m, 4H).

Synthesis of (2-(4-methylpiperazin-1-yl) thiazol-5-yl) methanaminehydrochloride (307)

Synthesis of tert-butyl ((2-(4-methylpiperazin-1-yl) thiazol-5-yl)methyl) carbamate (306)

A stirred solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (200 mg, 0.80 mmol) in N-methyl-2-pyrrolidone (5 mL) wasadded 1-methylpiperazine 305 (5 mL) in a sealed tube under argonatmosphere was heated to 100° C. and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with water (20 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were dried over sodium sulphate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 5% MeOH/CH₂Cl₂ to affordcompound 306 (200 mg, 80%) as colorless syrup. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.5); ¹H NMR (DMSO-d₆, 500 MHz): 7.31 (t, J=6.1 Hz, 1H), 6.92(s, 1H), 4.09 (d, J=5.5 Hz, 2H), 3.35-3.31 (m, 4H), 2.39 (t, J=4.8 Hz,4H), 2.21 (s, 3H), 1.38 (s, 9H).

Synthesis of (2-(4-methylpiperazin-1-yl) thiazol-5-yl) methanaminehydrochloride (307)

To a stirring solution of compound 306 (200 mg, 0.64 mmol) in CH₂Cl₂ (5mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (5 mL) at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was washed with diethyl ether (2×5mL) and dried in vacuo to afford compound 307 (240 mg, as HCl salt) asan off-white solid. TLC: 30% EtOAc/hexanes (R_(f): 0.1); ¹H-NMR(DMSO-d₆, 500 MHz): δ 11.37 (br s, 1H), 8.37 (br s, 3H), 7.29 (s, 1H),4.12 (q, J=5.4 Hz, 2H), 4.00-3.98 (m, 2H), 3.50-3.41 (m, 4H), 3.23-3.02(m, 2H), 2.80 (s, 3H).

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl)-N, N-dimethylanilinehydrochloride (312)

Synthesis of tert-butyl ((2-(4-nitrophenyl) thiazol-5-yl) methyl)carbamate (309)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (1 g, 4.02 mmol) in 1, 2 dimethoxy ethane:H₂O (4:1, 20 mL)was added sodium carbonate (1.5 g, 14.08 mmol) and purged under argonatmosphere for 30 min. To this was added Pd(PPh₃)₄ (464 mg, 0.40 mmol)and (4-nitrophenyl) boronic acid (308) at RT and stirred for 16 h. Thereaction was monitored by TLC; after completion the reaction, thereaction mixture was diluted with water (50 mL) and extracted with EtOAc(2×100 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 30%EtOAc/hexanes to afford compound 309 (650 mg, 48%) as yellow solid. TLC:30% EtOAc/hexanes (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 8.32 (d,J=9.0 Hz, 2H), 8.16 (d, J=8.9 Hz, 2H), 7.84 (s, 1H), 7.63 (t, J=5.7 Hz,1H), 4.38 (d, J=6.0 Hz, 2H), 1.40 (s, 9H); LC-MS: 92.61%; 335.9 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.66 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-aminophenyl) thiazol-5-yl) methyl)carbamate (310)

To a stirring solution of compound 309 (500 mg, 1.49 mmol) in MeOH (20mL) under inert atmosphere was added 10% Pd/C (150 mg) at RT and stirredunder hydrogen atmosphere (balloon pressure) at RT for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite and washed with MeOH (50mL). The filtrate was concentrated in vacuo to obtain the crude. Thecrude washed with 10% EtOAc/hexanes (20 mL) and dried in vacuo to affordcompound 310 (350 mg, 77%) as an off-white solid. TLC: 30% EtOAc/hexanes(R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 7.54 (d, J=8.6 Hz, 2H), 7.48(s, 2H), 6.59 (d, J=8.6 Hz, 2H), 5.64 (br s, 2H), 4.26 (d, J=5.9 Hz,2H), 1.39 (s, 9H); LC-MS: 98.14%; 305.9 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.06 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-(dimethylamino) phenyl) thiazol-5-yl)methyl) carbamate (311)

To a stirring solution of compound 310 (200 mg, 0.65 mmol) in MeOH (10mL) under inert atmosphere were added paraformaldehyde (98 mg, 3.27mmol) and sodium cyanoborohydride (206 mg, 3.27 mmol) at RT and stirredfor 16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was quenched with ice-cold water (10 mL)and extracted with 10% MeOH/CH₂Cl₂ (2×100 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 20% EtOAc/hexanes to afford compound 311(120 mg, 55%) as white solid. TLC: 30% EtOAc/hexanes (R_(f): 0.8); ¹HNMR (DMSO-d₆, 500 MHz): δ 7.69 (d, J=9.0 Hz, 2H), 7.52 (s, 1H), 7.49 (t,J=5.5 Hz, 1H), 6.76 (d, J=9.0 Hz, 2H), 4.28 (d, J=5.8 Hz, 2H), 2.97 (s,6H), 1.40 (s, 9H); LC-MS: 98.93%; 334.1 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.06 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl)-N,N-dimethylanilinehydrochloride (312)

To a stirring solution of compound 311 (120 mg, 0.36 mmol) in CH₂Cl₂ (5mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (1 mL) at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was washed with diethylether (2×5mL) and dried in vacuo to afford compound 312 (90 mg, 93%) as whitesolid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ8.53 (br s, 3H), 7.83 (s, 1H), 7.76 (d, J=8.7 Hz, 2H), 6.86 (d, J=7.2Hz, 2H), 4.27 (q, J=5.4 Hz, 2H), 2.99 (s, 6H); LC-MS: 98.98%; 233.8(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.51 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl)-3-fluorobenzonitrilehydrochloride (316)

Synthesis of 3-fluoro-4-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzonitrile (314)

To a stirring solution of 4-bromo-3-fluorobenzonitrile 313 (15 g, 75.0mmol) in 1,4-dioxane (200 mL) under inert atmosphere were added bispinacolato diboron (28.56 g, 112.5 mmol), potassium acetate (25.76 g,262.5 mmol) at RT and purged under argon atmosphere for 20 min; to thiswas added Pd(dppf)₂Cl₂ (5.5 g, 7.51 mmol) and purged under argonatmosphere for 20 min, heated to 100° C. and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite, washed with EtOAc (2×500mL). The filtrate was concentrated in vacuo and the residue was dilutedwith H₂O (500 mL) and extracted with EtOAc (2×700 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel flash column chromatography using 15-20%EtOAc/hexanes to afford compound 314 (10.2 g, 55%) as an off-whitesolid. TLC: 20% EtOAc/hexanes (R_(f): 0.3); ¹H-NMR (DMSO-d₆, 400 MHz): δ7.82-7.75 (m, 2H), 7.67 (dd, J=7.7, 1.4 Hz, 1H), 1.30 (s, 12H).

Synthesis of tert-butyl ((2-(4-cyano-2-fluorophenyl) thiazol-5-yl)methyl) carbamate (315)

To a stirring solution of compound 224 (8 g, 32.16 mmol) in 1,2-dimethoxy ethane:H₂O (4:1, 100 mL) under inert atmosphere were addedcompound 314 (10.4 g, 42.09 mmol), sodium carbonate (12 g, 113.20 mmol)in a sealed tube at RT and purged under argon atmosphere for 15 min,added Pd(dppf)Cl₂ (2.36 g, 3.22 mmol) and heated to 100° C. and stirredfor 16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with water (100 mL) andextracted with EtOAc (2×800 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel flash columnchromatography using 25-30% EtOAc/hexanes and triturated using 10%EtOAc/hexanes to afford compound 315 (6.5 g, 61%) as an off-white solid.TLC: 30% EtOAc/hexanes (R_(f): 0.3); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.36(t, J=7.9 Hz, 1H), 8.10 (dd, J=11.3, 1.4 Hz, 1H), 7.91 (d, J=2.4 Hz,1H), 7.83 (dd, J=8.2, 1.6 Hz, 1H), 7.62 (br t, J=5.5 Hz, 1H), 4.40 (brd, J=5.9 Hz, 2H), 1.40 (s, 9H); LC-MS: 94.47%; 333.9 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.61 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl)-3-fluorobenzonitrilehydrochloride (316)

To a stirring solution of compound 315 (6.5 g, 19.51 mmol) in CH₂Cl₂ (70mL) was added 4 N HCl in 1, 4-dioxane (70 mL) under argon atmosphere at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude washed with EtOAc (2×100 mL) and dried in vacuo toafford compound 316 (4.7 g; 89% as HCl salt) as white solid. TLC: 30%EtOAc/hexanes (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.60 (br s,3H), 8.39 (t, J=7.9 Hz, 1H), 8.23-8.08 (m, 2H), 7.87 (dd, J=8.2, 1.5 Hz,1H), 4.42 (br s, 2H); LC-MS: 98.68%; 234.9 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.40 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(5-(aminomethyl) thiazol-2-yl) indolin-2-onehydrochloride (319)

Synthesis of tert-butyl ((2-(2-oxoindolin-5-yl) thiazol-5-yl) methyl)carbamate (318)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (1 g, 4.03 mmol) in 1, 4-dioxane:H₂O (4:1, 30 mL) underinert atmosphere were added 5-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) indolin-2-one 317 (1.3 g, 5.02 mmol) and potassiumphosphate (2.60 g, 12.26 mmol) in sealed tube at RT and purged underinert atmosphere for 20 min. To this was added Pd(PPh₃)₄ (465 mg, 0.40mmol) and heated to 110° C. and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo to obtain the crude. The crude was purified throughsilica gel flash column chromatography using 2-4% MeOH/CH₂Cl₂ to affordcompound 318 (600 mg, 43%) as pale yellow solid. TLC: 5% MeOH/CH₂Cl₂(R_(f): 0.2). ¹H-NMR (DMSO-d₆, 400 MHz): δ 10.58 (s, 1H), 7.71 (d, J=5.1Hz, 2H), 7.59 (s, 1H), 7.52 (t, J=5.8 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H),4.29 (d, J=5.8 Hz, 2H), 3.54 (s, 2H), 1.39 (s, 9H); LC-MS: 91.80%; 346.9(M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 2.31 min. 2.5mM Aq. NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 5-(5-(aminomethyl) thiazol-2-yl) indolin-2-onehydrochloride (319)

To a stirring solution of compound 318 (600 mg, 1.74 mmol) in CH₂Cl₂ (10mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (10 mL) at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude which was triturated with EtOAc (2×5 mL) anddried in vacuo to afford compound 319 (600 mg; crude) as yellow solid.TLC: 10% MeOH/to CH₂Cl₂ (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 10.69(s, 1H), 8.58 (br s, 3H), 7.90 (s, 1H), 7.80-7.73 (m, 2H), 6.93 (d,J=8.7 Hz, 1H), 4.31 (q, J=5.5 Hz, 2H), 3.57 (s, 2H);

Synthesis of (2-(4-methoxybenzyl) thiazol-5-yl) methanaminehydrochloride (326)

Synthesis of (5-(((tert-butyldimethylsilyl) oxy) methyl) thiazol-2-yl)(4methoxyphenyl) methanol (322)

To a stirring solution 5-(((tert-butyldimethylsilyl) oxy) methyl)thiazole 320 (6 g, 26.20 mmol) in dry THF (100 mL) under inertatmosphere was added n-butyl lithium (1.6 M solution in hexane, 24 mL,39.30 mmol) dropwise for 10 min at −78° C. and stirred for 30 min. Tothis was added 4-methoxybenzaldehyde 321 (3.9 g, 28.80 mmol) at −78° C.and stirred at the same temperature for 3 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasquenched with saturated ammonium chloride solution (50 mL) and extractedwith EtOAc (2×200 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using20% EtOAc/hexanes to afford compound 322 (6 g, 63%) as colorless liquid.TLC: 20% EtOAc/hexanes (R_(f): 0.2); ¹H NMR (500 MHz, DMSO-d₆): δ 7.51(s, 1H), 7.31 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.61 (d, J=4.6Hz, 1H), 5.81 (d, J=4.3 Hz, 1H), 4.83 (s, 2H), 3.72 (s, 3H), 0.88-0.85(m, 9H), 0.07 (s, 6H).

Synthesis of (2-(4-methoxybenzyl) thiazol-5-yl) methanol (323)

To a stirring solution of compound 322 (6 g, 16.43 mmol) in 1,2-dichloroethane (30 mL) under inert atmosphere were addedtrieythlsilane (2.65 mL, 82.19 mmol), trifluoroacetic acid (6.28 mL,82.19 mmol) at 0° C.; heated to 60° C. and stirred for 8 h. The reactionwas monitored by TLC; after completion of the reaction, the volatileswere removed in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 60% EtOAc/hexanes toafford compound 323 (2.8 g, 73%) as sticky solid. TLC: 40% EtOAc/hexanes(R_(f): 0.2); ¹H NMR (500 MHz, DMSO-d₆): δ 7.48 (s, 1H), 7.22 (d, J=8.7Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 5.41 (br s, 1H), 4.57 (s, 2H), 4.18 (s,2H), 3.72 (s, 3H); LC-MS: 90.27%; 235.9 (M⁺+1); (column; Kinetex EVOC-18 (50×3.0 mm, 2.6 um); RT 2.03 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5%2.5 mM Aq.NH₄OOCH; 0.8 mL/min).

Synthesis of 5-(chloromethyl)-2-(4-methoxybenzyl) thiazole (324)

To a stirring solution of compound 323 (2.8 g, 11.90 mmol) in CH₂Cl₂ (30mL) under inert atmosphere were added triethylamine (5.0 mL, 35.70mmol), methanesulfonyl chloride (1.16 mL, 14.29 mmol) at 0° C.; warmedto RT and stirred for 4 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withCH₂Cl₂ (100 mL) and washed with water (75 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to afford crude compound 324 (2.1 g) as colorless liquid. TLC: 30%EtOAc/hexanes (R_(f): 0.8); ¹H NMR (500 MHz, DMSO-d₆): δ 7.70 (s, 1H),7.24 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 5.00 (s, 2H), 4.22 (s,2H), 3.73 (s, 3H)

Synthesis of 5-(azidomethyl)-2-(4-methoxybenzyl) thiazole (325)

To a stirring solution of compound 324 (2.1 g, crude) in DMF (20 mL)under inert atmosphere was added sodium azide (1.61 g, 24.90 mmol) at 0°C.; warmed to RT and stirred for 4 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (100 mL) and extracted with EtOAc (2×100 mL). The combined organicextracts were dried over sodium sulphate, filtered and concentrated invacuo to afford compound 325 (1.5 g) as colorless sticky solid. TLC: 20%EtOAc/hexanes (R_(f): 0.4); 41 NMR (400 MHz, DMSO-d₆): δ 7.68 (s, 1H),7.25 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 4.65 (s, 2H), 4.24 (s,2H), 3.73 (s, 3H); LC-MS: 89.03%; 260.9 (M⁺+1); (column; Kinetex EVOC-18 (50×3.0 mm, 2.6 um); RT 2.96 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5%2.5 mM Aq.NH₄OOCH; 0.8 mL/min).

Synthesis of (2-(4-methoxybenzyl) thiazol-5-yl) methanaminehydrochloride (326)

To a stirring solution of compound 325 (1.5 g, crude) in THF:H₂O (10:1,22 mL) was added triphenyl phosphine (1.5 g, 5.76 mmol) at 0° C.; warmedto RT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction; the volatiles were removed in vacuo toobtain the crude amine (1.3 g crude).

To the above crude amine (1.3 g) in CH₂Cl₂ (10 mL) was added 4 N HCl in1, 4-dioxane (3 mL) under inert atmosphere at 0° C. and stirred for 1 h.The reaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The crude washed with triturated withEtOAc (5 mL), CH₂Cl₂ (5 mL) and dried in vacuo to afford compound 326(830 mg, 53% HCl salt) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂(R_(f). 0.1); ¹H NMR (400 MHz, DMSO-d₆): δ 8.33 (br s, 1H), 7.73 (s,1H), 7.25 (d, J=8.7 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 4.33-4.11 (m, 6H),3.73 (s, 3H)

Synthesis of (5-(aminomethyl) thiazol-2-yl) (phenyl) methanone (332)

Synthesis of (5-(((tert-butyldimethylsilyl) oxy) methyl) thiazol-2-yl)(phenyl) methanone (328)

To a stirring solution of 5-(((tert-butyldimethylsilyl) oxy) methyl)thiazole 320 (200 mg, 0.87 mmol) in dry THF (15 mL) under inertatmosphere was added n-butyl lithium (1.6 M solution in hexane, 0.82 mL,1.30 mmol) dropwise for 5 min at −78° C. and stirred for 1 h. To thiswas added benzonitrile 327 (180 mg, 1.74 mmol) at −78° C. and stirredfor 2 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was quenched with 1 N aqueous HCl (10 mL)at −78° C. and extracted with EtOAc (2×50 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelflash column chromatography using 5-10% EtOAc/hexanes to afford crudecompound 328 (300 mg) as pale yellow liquid. TLC: 20% EtOAc/hexanes(R_(f): 0.8); ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.36 (d, J=7.5 Hz, 2H), 8.08(s, 1H), 7.86-7.82 (m, 2H), 7.76-7.69 (m, 1H), 5.04 (s, 2H), 0.91 (s,9H), 0.12 (s, 6H);

Synthesis of (5-(hydroxymethyl) thiazol-2-yl) (phenyl) methanone (329)

To a stirring solution of compound 328 (300 mg, 0.90 mmol) in THF (5 mL)under inert atmosphere was added tetrabutylammonium fluoride (1.0 Msolution in THF, 1.35 mL, 1.35 mmol) at 0° C. and stirred for 1 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was quenched with water (20 mL) and extracted withEtOAc (2×50 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel flash column chromatography using10% EtOAc/hexanes to afford crude compound 329 (100 mg, 52% over 2steps) as pale yellow solid. TLC: 20% EtOAc/hexanes (R_(f): 0.1); LC-MS:99.90%; 219.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 2.02 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min). ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.38-8.33 (m, 2H), 8.09-8.02 (m,1H), 7.75-7.70 (m, 1H), 7.62-7.57 (m, 2H), 5.86 (t, J=5.8 Hz, 1H), 4.81(dd, J=5.7, 0.9 Hz, 2H).

Synthesis of (2-benzoylthiazol-5-yl) methyl methanesulfonate (330)

To a stirring solution of compound 329 (100 mg, 0.45 mmol) in CH₂Cl₂ (5mL) under inert atmosphere were added triethyl amine (2.5 mL, 17.32mmol) at 0° C. and stirred for 10 min. To this was added methanesulfonylchloride (0.13 mL, 0.08 mmol) at 0° C.; warmed to RT and stirred for 16h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was diluted with water (50 mL), extracted withCH₂Cl₂ (2×50 mL), washed with saturated NaHCO₃ solution (30 mL) andbrine (20 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to afford crude compound 330(150 mg) as pale yellow liquid. TLC: 20% EtOAc/hexanes (R_(f): 0.1);¹H-NMR (DMSO-d₆, 400 MHz): δ 8.38-8.33 (m, 2H), 8.25 (s, 1H), 7.76-7.71(m, 1H), 7.64-7.56 (m, 2H), 5.22 (s, 2H), 2.42 (s, 3H).

Synthesis of (5-(azidomethyl) thiazol-2-yl) (phenyl) methanone (331)

To a stirring solution of compound 330 (150 mg, 0.50 mmol) in DMF (150mL) under inert atmosphere was added sodium azide (49 mg, 0.75 mmol) atRT and stirred for 16 h. The reaction was monitored by TLC and LC-MS;after completion of the reaction, the reaction mixture was diluted withEtOAc (100 mL) and washed with ice-cold water (2×50 mL). The combinedorganic extracts were dried over sodium sulphate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel flash column chromatography using 5-10% EtOAc/hexanesto afford compound 331 (100 mg, 89%, over 2 steps) as pale yellow solid.TLC: 20% EtOAc/hexanes (R_(f): 0.6); ¹H-NMR (DMSO-d₆, 400 MHz): δ8.40-8.38 (m, 2H), 8.23 (s, 1H), 7.79-7.74 (m, 1H), 7.65-7.60 (m, 2H),4.94 (s, 2H). LC-MS: 94.73%; 244.9 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 2.65 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (5-(aminomethyl) thiazol-2-yl) (phenyl) methanone (332)

To a stirring solution of compound 331 (100 mg, 0.41 mmol) in THF:H₂O(5:1, 12 mL) was added triphenyl phosphine (161 mg, 0.61 mmol) at 0° C.;warmed to RT and stirred for 20 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo,further dried by azeotropic distillation using toluene (2×5 mL) toobtain the crude.

The above crude compound was diluted with CH₂Cl₂ (1 mL) and under inertatmosphere was added 4 N HCl in 1, 4-dioxane (1 mL) at 0° C., warmed toRT and stirred for 1 h. The volatiles were removed in vacuo and thecrude was washed with diethyl ether (10 mL), hexane (10 mL) andtriturated with CH₂Cl₂:hexanes (4:1, 5 mL) to afford compound 332 (100mg, 96%) as pale yellow solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); LC-MS:30.80%; 218.8 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.51 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 1-(2-(5-(aminomethyl) thiazol-2-yl)phenyl)-2-methylpropan-2-ol hydrochloride (338)

Synthesis of methyl 2-(2-bromophenyl) acetate (334)

To a stirring solution of 2-(2-bromophenyl) acetic acid 333 (5 g, 23.25mmol) in MeOH (100 mL) under inert atmosphere was added thionyl chloride(2.00 mL, 27.90 mmol) dropwise at 0° C. for 15 min; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with CH₂Cl₂ (300 mL) and the pH was neutralized with saturatedNaHCO₃ solution (200 mL). The organic layer was separated dried oversodium sulphate, filtered and concentrated in vacuo to afford compound334 (5 g, 94%) as colorless thick syrup. TLC: 20% EtOAc/hexanes (R_(f):0.8); ¹H-NMR (DMSO-d₆, 400 MHz): δ 7.62 (dd, J=8.0, 1.1 Hz, 1H),7.43-7.39 (m, 1H), 7.36 (td, J=7.4, 1.1 Hz, 1H), 7.23 (td, J=7.6, 1.8Hz, 1H), 3.83 (s, 2H), 3.63 (s, 3H);

Synthesis of methyl 2-(2-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl) acetate (335)

To a stirring solution of compound 334 (4.5 g, 19.65 mmol) in 1,4-dioxane (100 mL) under inert atmosphere were added bispinacolatodiboron (5.98 g, 23.58 mmol), potassium acetate (8.30 g, 84.50 mmol) atRT and purged under argon atmosphere for 15 min; to this was addedPd(dppf)Cl₂ (1.43 g, 1.96 mmol) and purged under argon atmosphere for 5min, heated to 80° C. and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasfiltered through celite, washed with 50% MeOH/CH₂Cl₂ (2×80 mL). Thefiltrate was concentrated in vacuo to obtain the crude. The crude waspurified through silica gel flash column chromatography using 10-12%EtOAc/hexanes to afford compound 335 (3 g, 55%) as colorless syrup. TLC:10% EtOAc/hexanes (R_(f): 0.4); ¹H-NMR (CDCl₃, 400 MHz): δ 7.85 (br d,J=7.2 Hz, 1H), 7.42-7.38 (m, 1H), 7.32-7.26 (m, 1H), 7.21 (br d, J=7.5Hz, 1H), 4.00 (s, 2H), 3.68 (s, 3H), 1.34 (s, 12H);

Synthesis of methyl 2-(2-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenyl) acetate (336)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (1 g, 4.02 mmol) in 1, 2-dimethoxy ethane:H₂O (4:1, 30 mL)under inert atmosphere were added compound 335 (1.33 g, 4.82 mmol) andpotassium phosphate (2.55 g, 12.06 mmol) in sealed tube at RT and purgedunder argon atmosphere for 15 min. To this was added Pd(dppf)Cl₂ (294mg, 0.40 mmol) and heated to 100° C. and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the volatileswere removed in vacuo to obtain the crude. The crude was purifiedthrough silica gel flash column chromatography using 10-15%EtOAc/hexanes to afford compound 336 (700 mg, 48%) as an off-whitesolid. TLC: 30% EtOAc/hexanes (R_(f): 0.4). ¹H-NMR (DMSO-d₆, 400 MHz): δ7.71-7.64 (m, 2H), 7.56 (t, J=5.6 Hz, 1H), 7.45-7.37 (m, 3H), 4.33 (d,J=5.9 Hz, 2H), 4.06 (s, 2H), 3.52 (s, 3H), 1.40 (s, 9H);

Synthesis of tert-butyl ((2-(2-(2-hydroxy-2-methylpropyl) phenyl)thiazol-5-yl) methyl) carbamate (337)

To a stirring solution of compound 336 (700 mg, 1.93 mmol) in anhydrousTHF (20 mL) under inert atmosphere was added methylmagnesium bromide(5.79 mL, 17.40 mmol, 3 M sol. In diethylether) at −10° C.; warmed to RTand stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withaqueous saturated ammonium chloride solution (70 mL) and extracted withEtOAc (2×70 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel (100-200 mesh) columnchromatography using 30-40% EtOAc/hexanes to afford compound 337 (200mg, 29%) as an off-white solid. TLC: 30% EtOAc/hexanes (R_(f): 0.4);¹H-NMR (DMSO-d₆, 400 MHz): δ 7.72 (s, 1H), 7.56 (t, J=5.6 Hz, 1H), 7.52(dd, J=7.7, 1.1 Hz, 1H), 7.46-7.38 (m, 2H), 7.34 (dd, J=7.5, 1.9 Hz,1H), 4.99 (s, 1H), 4.35 (d, J=5.8 Hz, 2H), 3.07 (s, 2H), 1.40 (s, 9H),1.00 (s, 6H);

Synthesis of 1-(2-(5-(aminomethyl) thiazol-2-yl)phenyl)-2-methylpropan-2-ol hydrochloride (338)

To a stirring solution of compound 337 (200 mg, 0.55 mmol) in CH₂Cl₂ (10mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (2 mL) at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was triturated with diethyl ether (2×10 mL) and driedin vacuo to afford compound 338 (160 mg, HCl salt) as an off-whitesolid. TLC: 40% EtOAc/hexanes (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ8.45 (br s, 3H), 8.00 (s, 1H), 7.53 (dd, J=7.7, 1.1 Hz, 1H), 7.50-7.41(m, 2H), 7.39-7.34 (m, 1H), 4.37 (q, J=5.7 Hz, 2H), 3.11 (s, 2H), 0.99(s, 6H);

Synthesis of [2, 2′-bithiazol]-5-ylmethanamine hydrochloride (345)

Synthesis of methyl [2, 2′-bithiazole]-5-carboxylate (341)

To a stirring solution of methyl 2-bromothiazole-5-carboxylate 339 (3 g,13.51 mmol) in Toulene (50 mL) under inert atmosphere in a sealed tubewere added 2-bromothiazole 340 (5.9 g, 40.41 mmol),diisopropylethylamine (1.7 mL, 13.50 mmol), tetrabutylammonium bromide(2.10 g, 6.52 mmol), Pd(OAc)₂ (150 mg, 0.66 mmol) at RT; heated to 100°C. and stirred for 24 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was filtered throughcelite and the filtrate was concentrated in vacuo to obtain the crude.The crude was purified through silica gel column flash chromatographyusing 20% EtOAc/hexanes to afford crude compound 341 (1.5 g, crude)which was carried to next step without further purification. TLC: 40%EtOAc/hexanes (R_(f): 0.5);

Synthesis of [2, 2′-bithiazol]-5-ylmethanol (342)

To a stirring solution of compound 341 (1.5 g, 6.63 mmol) in MeOH (10mL) under inert atmosphere was added sodium borohydride (1.5 g, 39.82mmol) portion wise for 15 min at 0° C.; warmed to RT and stirred for 16h. The reaction was monitored by TLC; after completion of the reaction,the volatiles were removed in vacuo. The crude was diluted with EtOAc(100 mL) and washed with water (2×50 mL). The combined organic extractswere dried over sodium sulfate and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel column flashchromatography using 20% EtOAc/hexanes to afford compound 342 (800 mg,30%, over 2 steps) as colorless liquid. TLC: 40% EtOAc/hexanes (R_(f):0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 7.97 (d, J=3.2 Hz, 1H), 7.90 (d,J=3.05 Hz, 1H), 7.80 (s, 1H), 5.72 (t, J=5.8 Hz, 1H), 4.73 (dd, J=5.8,0.9 Hz, 2H); LC-MS: 60.68%; 234.9 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 1.44 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min).

Synthesis of [2, 2′-bithiazol]-5-ylmethyl methanesulfonate (343)

To a stirring solution of compound 342 (800 mg, 4.04 mmol) in CH₂Cl₂ (10mL) under inert atmosphere were added triethyl amine (1.73 mL, 12.12mmol) and methanesulfonyl chloride (0.13 mL, 0.08 mmol) at 0° C.; warmedto RT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(50 mL), extracted with EtOAc (2×50 mL) The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toafford crude compound 343 (1.1 g, 99%) as brown liquid. TLC: 20%EtOAc/hexanes (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.02-7.99 (m,2H), 7.96 (d, J=3.2 Hz, 1H), 5.16 (s, 2H), 2.45 (s, 3H); LC-MS 88.94%;278.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT2.26 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(azidomethyl)-2, 2′-bithiazole (344)

To a stirring solution of compound 343 (1.1 g, 3.98 mmol) in DMF (10 mL)under inert atmosphere was added sodium azide (778 mg, 11.95 mmol) atRT; heated to 60° C. and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith water (50 mL) and extracted with EtOAc (100 mL) The combinedorganic extracts were dried over sodium sulphate, filtered andconcentrated in vacuo to afford compound 344 (600 mg, 67%) as colorlessliquid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ8.00 (d, J=3.2 Hz, 1H), 7.98 (s, 1H), 7.95 (d, J=3.1 Hz, 1H), 4.82 (s,2H); LC-MS: 88.41%; 223.8 (M⁺+1); (column; Ascentis Express C18, (50×3.0mm, 2.7 μm); RT 2.20 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min).

Synthesis of [2, 2′-bithiazol]-5-ylmethanamine hydrochloride (345)

To a stirring solution of compound 344 (600 mg, 2.69 mmol) in THF:H₂O(4:1, 5 mL) was added triphenyl phosphine (846 mg, 3.22 mmol) at 0° C.;warmed to RT and stirred for 2 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The pH of the residue was adjusted to 2 with 1 N HCl. The aqueous layerwas washed with EtOAc (2×25 mL). The aqueous layer was concentrated invacuo and further dried by azeotropic distillation using toluene (10 mL)to afford compound 345 (600 mg, crude) as pale yellow solid. The crudewas taken forward for next step without further purification. TLC: 5%

Synthesis of picolinamide (347)

To a stirring solution of picolinonitrile 346 (30 g, 296.91 mmol) inDMSO (300 mL) was added potassium carbonate (39.8 g, 288.35 mmol)followed by slow addition of 30% H₂O₂ (300 mL, 10 vol) for 20 min at 0°C.; warmed to RT and stirred for 3 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withEtOAc (200 mL) and washed with water (2×100 mL). The aqueous layer wasextracted with EtOAc (4×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to affordcrude compound 347 (45 g) as an off-white solid. TLC: 50% EtOAc/hexanes(R_(f): 0.2).

Synthesis of pyridine-2-carbothioamide (348)

To a stirring solution of compound 347 (45 g, 368.45 mmol) in THF (500mL) under inert atmosphere was added P₂S₅ (81.97 g, 368.85 mmol) at 0°C., RT; heated to reflux and stirred for 16 h. The reaction wasmonitored by TLC after 16 h, the reaction mixture was diluted with EtOAc(200 mL), washed with saturated NaHCO₃ solution (2×80 mL). The aqueouslayer was extracted with EtOAc (3×100 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 10% EtOAc/hexanes to afford compound 348 (13 g,26%) as pale yellow solid. TLC: 40% EtOAc/hexanes (R_(f): 0.8). ¹H NMR(400 MHz, DMSO-d₆): δ 10.17 (br s, 1H), 9.91 (br s, 1H), 8.64-8.57 (m,1H), 8.50 (td J=8.0, 1.0 Hz, 1H), 7.97 (td, J=7.8, 1.8 Hz, 1H),7.61-7.57 (m, 1H).

Synthesis of 2-(pyridin-2-yl) thiazole-5-carbaldehyde (350)

A mixture of compound 348 (6 g, 43.41 mmol) and pyridine (12 mL) in THF(120 mL) was heated to 50° C. for 15 min, added 2-bromomalonaldehyde 349(9.2 g, 60.92 mmol), heated to reflux and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with EtOAc (100 mL) and washed with water (30 mL),brine (30 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silicagel flash column chromatography using5-20% EtOAc/hexanes to afford compound 350 as brown solid. TLC: 20%EtOAc/hexanes (R_(f): 0.3). ¹H NMR (400 MHz, DMSO-d₆): δ 10.11 (s, 1H),8.82 (s, 1H), 8.73-8.70 (m, 1H), 8.24 (d, J=7.9 Hz, 1H), 8.07-8.03 (m,1H), 7.63-7.60 (m, 1H); LC-MS: 94.69%; 190.8 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.93 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(pyridin-2-yl) thiazol-5-yl) methanol (351)

To a stirring solution of compound 350 (1.5 g, 7.81 mmol) in MeOH (50mL) under inert atmosphere was added sodium borohydride (600 mg, 15.78mmol) portion wise for 15 min at 0° C.; warmed to RT and stirred for 3h. The reaction was monitored by TLC; after completion of the reaction,the volatiles were removed in vacuo. The crude was diluted with EtOAc(100 mL) and washed with water (2×25 mL). The combined organic extractswere dried over sodium sulfate and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel flash columnchromatography using 10-40% EtOAc/hexanes to afford compound 351 (1 g,30%, over 2 steps) as pale brown solid. TLC: 30% EtOAc/hexanes (R_(f):0.2); ¹H NMR (400 MHz, DMSO-d₆): δ 8.65-8.58 (m, 1H), 8.10 (d, J=7.9 Hz,1H), 7.97-7.92 (m, 1H), 7.80 (s, 1H), 7.49-7.45 (m, 1H), 5.63 (t, J=5.7Hz, 1H), 4.72 (d, J=5.6 Hz, 2H); LC-MS: 99.64%; 192.9 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.47 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 5-(chloromethyl)-2-(pyridin-2-yl) thiazole (352)

To a stirring solution of compound 351 (1.0 g, 5.20 mmol) in CH₂Cl₂ (20mL) under inert atmosphere were added triethylamine (1.46 mL, 10.41mmol), methanesulfonyl chloride (712 mg, 6.25 mmol) at 0° C.; warmed toRT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with CH₂Cl₂(100 mL), washed with saturated NaHCO₃ solution (2×50 mL), brine (50mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to afford crude compound 352 (900 mg,83%) as pale brown solid. TLC: 50% EtOAc/hexanes (R_(f): 0.8); ¹H NMR(400 MHz, DMSO-d₆): δ 8.70-8.60 (m, 1H), 8.13 (d, J=7.9 Hz, 1H), 8.03(s, 1H), 8.01-7.97 (m, 1H), 7.55-7.52 (m, 1H), 5.17 (d, J=0.6 Hz, 2H);LC-MS: 97.86%; 210.9 (M⁺+1); (column; Ascentis Express C-18, (50×3.0 mm,2.7 μm); RT 2.27 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 5-(azidomethyl)-2-(pyridin-2-yl) thiazole (353)

To a stirring solution of compound 352 (900 mg, 4.28 mmol) in DMF (20mL) under inert atmosphere was added sodium azide (557 mg, 8.56 mmol) at0° C.; heated to 70° C. and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasdiluted with EtOAc (2×75 mL) washed with water (50 mL), brine (20 mL).The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude compound 353 (850 mg, 91%)as pale brown solid. TLC: 20% EtOAc/hexanes (R_(f): 0.5); ¹H NMR (400MHz, DMSO-d₆): δ 8.66-8.61 (m, 1H), 8.12 (d, J=7.9 Hz, 1H), 8.00-7.95(m, 2H), 7.53-7.51 (m, 1H), 4.80 (s, 2H); LC-MS: 96.94%; 217.8 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.21 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(pyridin-2-yl) thiazol-5-yl) methanamine hydrochloride(354)

To a stirring solution of compound 353 (850 mg, 3.91 mmol) in THF:H₂O(15:5, 25 mL) was added triphenyl phosphine (1.23 g, 4.69 mmol) at 0°C.; warmed to RT and stirred for 4 h. The reaction was monitored by TLC;after completion of the reaction; the volatiles were removed in vacuo toobtain the crude amine (1.02 g crude). TLC: 20% EtOAc/hexanes (R_(f):0.1);

To the above crude amine (1.02 g) in CH₂Cl₂ (50 mL) was added 4 N HCl in1, 4-dioxane (5 mL) under inert atmosphere at 0° C. and stirred for 1 h.The reaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo to obtain the crude. The crude wastriturated with diethyl ether (2×50 mL), CH₂Cl₂ (2×60 mL), EtOAc (2×50mL) and dried in vacuo to afford compound 354 (850 mg, 96%; HCl salt) asan hygroscopic off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR(400 MHz, DMSO-d₆): δ 8.65 (br s, 3H), 8.12 (d, J=7.0 Hz, 1H), 8.04 (s,1H), 8.01-7.94 (m, 1H), 7.69-7.46 (m, 2H), 4.36-4.32 (m, 2H); LC-MS:86.55%; 191.8 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT1.09 min. 2.5 mM Aq. NH₄OOCH+5% ACN:ACN: 5% 2.5 mM Aq. NH4OOCH; 0.8mL/min).

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl) phenol hydrochloride (357)

Synthesis of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl)carbamate (356)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (500 mg, 2.01 mmol) in 1, 2-dimethoxy ethane:H₂O (4:1, 20mL) were added sodium carbonate (640 mg, 6.03 mmol) and(4-hydroxyphenyl) boronic acid 355 (416 mg, 3.01 mmol) and purged underargon atmosphere for 30 min in a sealed tube. To this was addedPd(PPh₃)₄ (231 mg, 0.20 mmol) at RT; heated to 90° C. and stirred for 6h. The reaction was monitored by TLC; after completion of the reaction,the volatiles were removed in vacuo. The residue was diluted with EtOAc(200 mL), washed with water (100 mL). The organic extract was dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using40% EtOAc/hexanes to afford compound 356 (250 mg, 41%) as an off-whitesolid. TLC: 50% EtOAc/hexanes (R_(f): 0.5); ¹H-NMR (DMSO-d₆, 500 MHz):9.92 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.50 (t, J=5.5 Hz,1H), 6.83 (d, J=8.7 Hz, 2H), 4.28 (d, J=5.8 Hz, 2H), 1.38 (s, 9H).

Synthesis of 4-(5-(aminomethyl) thiazol-2-yl) phenol hydrochloride (357)

To a stirring solution of compound 356 (150 mg, 0.49 mmol) in CH₂Cl₂ (4mL) was added 4 N HCl in 1, 4-Dioxane (1.25 mL, 4.90 mmol) under inertatmosphere at 0° C.; warmed to RT and stirred for 2 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The crude was washed with diethyl ether (2×10 mL) anddried in vacuo to afford compound 357 (110 mg, 93%; HCl salt) as whitesolid. TLC: 30% EtOAc/hexanes (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ10.07 (br s, 1H), 8.51 (br s, 3H), 7.84 (s, 1H), 7.74 (d, J=8.4 Hz, 2H),6.88 (d, J=8.7 Hz, 2H), 4.28 (q, J=5.4 Hz, 2H).

Synthesis of 2-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N,N-dimethylethan-1-amine hydrochloride (360)

Synthesis of tert-butyl ((2-(4-(2-(dimethylamino) ethoxy) phenyl)thiazol-5-yl) methyl) carbamate (359)

To a mixture of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl)carbamate 356 (100 mg, 0.32 mmol) and 2-(dimethylamino) ethan-1-ol 358(43 mg, 0.49 mmol) in THF (5 mL) under inert atmosphere were addeddiisopropyl azodicarboxylate (198 mg, 0.98 mmol) and triphenyl phosphine(256 mg, 0.98 mmol) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The residue was diluted with CH₂Cl₂(100 mL) and washed with water (2×50 mL). The organic extract was driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel column chromatographyusing 3% MeOH/CH₂Cl₂ to afford compound 359 (60 mg, 49%) as white solid.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (DMSO-d₆, 500 MHz): δ 7.83 (d,J=8.7 Hz, 2H), 7.61 (s, 1H), 7.53 (t, J=5.2 Hz, 1H), 7.06 (d, J=9.0 Hz,2H), 4.31 (d, J=5.8 Hz, 2H), 4.19 (t, J=5.4 Hz, 2H), 2.91 (br s, 2H),2.42 (br s, 6H), 1.40 (s, 9H).

Synthesis of 2-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N,N-dimethylethan-1-amine hydrochloride (360)

To a stirring solution of compound 359 (60 mg, 0.15 mmol) in CH₂Cl₂ (3mL) was added 4 N HCl in 1, 4-Dioxane (0.4 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was washed with diethyl ether (2×5 mL) and dried invacuo to afford compound 360 (45 mg, 90%; HCl salt) as white solid. TLC:10% MeOH/CH₂Cl₂ (R_(f): 0.2); LC-MS: 94.06%; 277.9 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 0.42 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(4-methoxyphenyl) thiazol-5-yl) methanaminehydrochloride (363)

Synthesis of tert-butyl ((2-(4-methoxyphenyl) thiazol-5-yl) methyl)carbamate (362a)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (1 g, 4.02 mmol) in DMF:H₂O (4:1, 20 mL) were added sodiumcarbonate (464 mg, 0.40 mmol) and (4-methoxyphenyl) boronic acid 361(734 mg, 4.82 mmol) and purged under argon atmosphere for 20 min. Tothis was added Pd(PPh₃)₄ (464 mg, 0.40 mmol) at RT; heated to 80° C. andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with EtOAc (200 mL), washed with water (75 mL). The organicextract was dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 40% EtOAc/hexanes to afford compound 362a(700 mg, 58%) as yellow solid. TLC: 30% EtOAc/hexanes (R_(f): 0.2);¹H-NMR (DMSO-d₆, 500 MHz): δ 7.81 (d, J=8.7 Hz, 2H), 7.59 (s, 1H), 7.51(t, J=6.1 Hz, 1H), 7.02 (d, J=8.7 Hz, 2H), 4.29 (d, J=5.5 Hz, 2H), 3.80(s, 3H), 1.38 (s, 9H).

Synthesis of (2-(4-methoxyphenyl) thiazol-5-yl) methanaminehydrochloride (363)

To a stirring solution of compound 362a (700 mg, 2.18 mmol) in CH₂Cl₂(20 mL) under argon atmosphere was added 4 N HCl in 1, 4-dioxane (2 mL)at 0° C.; warmed to RT and stirred for 4 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo to afford compound 363 (550 mg, 99%) as an off-white solid. TLC:40% EtOAc/hexanes (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.52 (br s,3H), 7.90 (s, 1H), 7.87 (d, J=9.0 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 4.32(q, J=5.7 Hz, 2H), 3.83 (s, 3H).

Synthesis of tert-butyl ((2-(4-methoxyphenyl) thiazol-5-yl) methyl)carbamate (362b)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (150 mg, 0.49 mmol) in acetone (10 mL) under inertatmosphere were added potassium carbonate (203 mg, 1.47 mmol) and methyliodide (0.09 mL, 1.47 mmol) at 0° C.; heated to 70° C. and stirred for 2h. The reaction was monitored by TLC; after completion of the reaction,the volatiles were removed in vacuo. The residue was diluted with water(100 mL) and extracted with EtOAc (2×50 mL). The organic extract wasdried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 20% EtOAc/hexanes to afford compound 362b (105 mg,67%) as white solid. TLC: 40% EtOAc/hexanes (R_(f): 0.8); ¹H NMR(DMSO-d₆, 400 MHz): δ 7.82 (d, J=8.7 Hz, 2H), 7.61 (s, 1H), 7.53 (t,J=5.5 Hz, 1H), 7.04 (d, J=8.7 Hz, 2H), 4.31 (d, J=5.8 Hz, 2H), 3.81 (s,3H), 1.40 (s, 9H).

Synthesis of (2-(4-methoxyphenyl) thiazol-5-yl) methanaminehydrochloride (363)

To a stirring solution of compound 362b (100 mg, 0.31 mmol) in CH₂Cl₂ (5mL) under inert atmosphere was added 4 N HCl in 1, 4-Dioxane (0.78 mL)at 0° C.; warmed to RT and stirred for 3 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was washed with diethyl ether (10mL) and dried in vacuo to afford compound 363 (65 mg, 81%) as whitesolid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ8.49 (br s, 3H), 7.90 (s, 1H), 7.87 (d, J=8.7 Hz, 2H), 7.07 (d, J=9.0Hz, 2H), 4.32 (q, J=5.4 Hz, 2H), 3.83 (s, 3H).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N,N-dimethylpropan-1-amine hydrochloride (367)

Synthesis of 3-chloro-N, N-dimethylpropan-1-amine (365)

To a stirring solution of 3-(dimethylamino) propan-1-ol 364 (2.0 g, 1.94mmol) in CHCl₃ (50 mL) under inert atmosphere was added thionyl chloride(4.22 mL, 58.23 mmol) at 0° C.; heated to 70° C. and stirred for 4 h.The reaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo to obtain the crude. The crude waswashed with diethyl ether (2×30 mL) to afford compound 365 (2.5 g, 83%)as white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500MHz): δ 10.97 (br s, 1H), 3.74 (t, J=6.4 Hz, 2H), 3.12 (t, J=7.8 Hz,2H), 2.72 (s, 6H), 2.20-2.12 (m, 2H).

Synthesis of tert-butyl ((2-(4-(3-(dimethylamino) propoxy) phenyl)thiazol-5-yl) methyl) carbamate (366)

To a stirring solution of compound 356 (400 mg, 1.30 mmol) and compound365 (411 mg, 2.61 mmol) in acetone (20 mL) under inert atmosphere wasadded potassium carbonate (541 mg, 3.91 mmol) at RT; heated to 80° C.and stirred for 8 h. The reaction was monitored by TLC; after completionof the reaction, the volatiles were removed in vacuo. The residue wasdiluted with water (100 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 5% MeOH/CH₂Cl₂ to affordcompound 366 (350 mg, 68%) as off-white sticky solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H NMR (DMSO-d₆, 400 MHz): δ 7.81 (d, J=8.8Hz, 2H), 7.60 (s, 1H), 7.53 (t, J=5.5 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H),4.31 (d, J=5.7 Hz, 2H), 4.06 (t, J=6.3 Hz, 2H), 2.52-2.48 (m, 2H), 2.28(s, 6H), 1.96-1.87 (m, 2H), 1.40 (s, 9H).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N,N-dimethylpropan-1-amine hydrochloride (367)

To a stirring solution of compound 366 (350 mg, 0.89 mmol) in CH₂Cl₂ (5mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (2 mL) at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was washed with EtOAc (2×5 mL) anddried in vacuo to afford compound 367 (300 mg, 92%) as an off-whitesolid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ10.86 (br s, 1H), 8.65 (br s, 3H), 7.91 (s, 1H), 7.87 (d, J=8.9 Hz, 2H),7.08 (d, J=8.8 Hz, 2H), 4.31 (q, J=5.6 Hz, 2H), 4.14 (t, J=6.1 Hz, 2H),3.28-3.15 (m, 2H), 2.76 (s, 3H), 2.77 (s, 3H), 2.23-2.14 (m, 2H).

Synthesis of 4-(5-((methylamino) methyl) thiazol-2-yl) phenol (369)

Synthesis of 1-(2-chlorothiazol-5-yl)-N-methylmethanamine (368)

To a stirring solution of 2-chloro-5-(chloromethyl) thiazole 221 (2 g,11.90 mmol) in EtOH (15 mL) in a sealed tube under inert atmosphere wereadded methyl amine 240 (2 M in THF, 1.8 mL, 14.28 mmol) at 0° C.; warmedto RT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(10 mL) extracted with EtOAc (2×50 mL). The combined organic extractswere dried over sodium sulphate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 5% MeOH/CH₂Cl₂ to afford compound 368 (600 mg, 31%)as colorless liquid. TLC: 30% EtOAc/hexanes (R_(f): 0.7); ¹H NMR(DMSO-d₆, 400 MHz): δ 7.57 (s, 1H), 4.08 (br s, 1H), 3.91 (s, 2H), 3.17(s, 3H).

Synthesis of 4-(5-((methylamino) methyl) thiazol-2-yl) phenol (369)

To a stirring solution of 1-(2-chlorothiazol-5-yl)-N-methylmethanamine368 (200 mg, 1.23 mmol) in 1, 2 dimethoxy ethane:H₂O (4:1, 15 mL) wereadded (4-hydroxyphenyl) boronic acid 355 (170 mg, 1.923 mmol), sodiumcarbonate (342 mg, 3.70 mmol) and purged under argon atmosphere for 30min. To this was added Pd(PPh₃)₄ (142 mg, 0.12 mmol) at RT; heated to100° C. and stirred for 16 h. The reaction was monitored by TLC; aftercompletion the reaction mixture was diluted with water (50 mL) andextracted with EtOAc (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 5% MeOH/CH₂Cl₂ to afford compound 369 (70 mg, 25%)as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H-NMR(DMSO-d₆, 500 MHz): 9.96 (br s, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.63 (s,1H), 6.85 (d, J=8.8 Hz, 2H), 4.08 (br s, 1H), 3.91 (s, 2H), 3.17 (s,3H).

Synthesis of (2-(4-(2-morpholinoethoxy) phenyl) thiazol-5-yl)methanamine hydrochloride (372)

Synthesis of tert-butyl ((2-(4-(2-morpholinoethoxy) phenyl)thiazol-5-yl) methyl) carbamate (371a)

To a mixture of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl) methyl)carbamate 356 (250 mg, 0.81 mmol) in THF (5 mL) under inert atmospherewas added diisopropyl azodicarboxylate (495 mg, 2.45 mmol) and triphenylphosphine (642 mg, 2.45 mmol) at 0° C. and stirred for 10 min. To thiswas added 2-morpholinoethan-1-ol 370 (128 mg, 0.98 mmol) at 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The residue was diluted with CH₂Cl₂ (100 mL) and washed with water (2×50mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 3% MeOH/CH₂Cl₂to afford compound 371a (170 mg, 50%) as white solid. TLC: 50%EtOAc/hexanes (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 7.79 (d, J=8.7Hz, 2H), 7.59 (s, 1H), 7.51 (t, J=5.5 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H),5.74 (s, 1H), 4.29 (d, J=6.1 Hz, 2H), 4.13 (t, J=5.8 Hz, 2H), 3.59-3.54(m, 4H), 2.69 (t, J=5.8 Hz, 2H), 2.52-2.42 (m, 4H), 1.38 (s, 9H).

Synthesis of (2-(4-(2-morpholinoethoxy) phenyl) thiazol-5-yl)methanamine hydrochloride (372)

To a stirring solution of compound 371a (170 mg, 0.40 mmol) in CH₂Cl₂(10 mL) was added 4 N HCl in 1, 4-Dioxane (1 mL) under inert atmosphereat 0° C.; warmed to RT and stirred for 3 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo. The crude was washed with EtOAc (5 mL) and dried in vacuo toafford compound 372 (100 mg, 56%; HCl salt) as white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.56 (br s, 3H),7.92 (s, 1H), 7.90 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H), 4.52 (t,J=4.8 Hz, 2H), 4.35-4.30 (m, 2H), 4.00-3.94 (m, 2H), 3.85 (t, J=11.3 Hz,2H), 3.60-3.55 (m, 2H), 3.50-3.47 (m, 2H), 3.25-3.15 (m, 2H).

Synthesis of (2-(4-(2-morpholinoethoxy) phenyl) thiazol-5-yl)methanamine hydrochloride (372): Approach-2 Synthesis of4-(2-chloroethyl) morpholine hydrochloride (370a)

To a stirring solution of 3-(dimethylamino) propan-1-ol 370 (3.0 g,23.07 mmol) in CHCl₃ (50 mL) under inert atmosphere was added thionylchloride (6.88 mL, 69.23 mmol) at 0° C.; heated to 70° C. and stirredfor 1 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo to obtain the crude. Thecrude was washed with diethyl ether (2×30 mL) to afford compound 370a (3g, 88%) as white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f). 0.2); ¹H-NMR(DMSO-d₆, 500 MHz): 11.65 (br s, 1H), 10.81 (br s, 1H), 4.06 (t, J=6.8Hz, 1H), 3.98-3.90 (m, 2H), 3.86-3.77 (m, 2H), 3.54-3.36 (m, 3H),3.22-3.03 (m, 2H).

Synthesis of tert-butyl ((2-(4-(2-morpholinoethoxy) phenyl)thiazol-5-yl) methyl) carbamate (371b)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (150 mg, 0.49 mmol) and 4-(2-chloroethyl)morpholine hydrochloride 370a (145 mg, 0.98 mmol) in acetone (15 mL)under inert atmosphere was added potassium carbonate (203 mg, 2.45 mmol)at RT; heated to 70-80° C. and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The residue was diluted with water (100 mL) andextracted with EtOAc (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 3% MeOH/CH₂Cl₂ to afford compound 371b (175 mg,85%) as colorless thick syrup. TLC: 3% MeOH/CH₂Cl₂(R_(f): 0.5); ¹H NMR(DMSO-d₆, 400 MHz): δ 7.79 (d, J=8.7 Hz, 2H), 7.59 (s, 1H), 7.51 (t,J=5.5 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 5.74 (s, 1H), 4.29 (d, J=6.1 Hz,2H), 4.13 (t, J=5.8 Hz, 2H), 3.59-3.54 (m, 4H), 2.69 (t, J=5.8 Hz, 2H),2.52-2.42 (m, 4H), 1.38 (s, 9H).

Synthesis of (2-(4-(2-morpholinoethoxy) phenyl) thiazol-5-yl)methanamine hydrochloride (372)

To a stirring solution of compound 371b (175 mg, 0.40 mmol) in CH₂Cl₂ (5mL) was added 4 N HCl in 1, 4-Dioxane (5 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was washed with diethyl ether (5 mL) and dried in vacuoto afford compound 372 (155 mg, 95%; HCl salt) as white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.56 (br s, 3H),7.92 (s, 1H), 7.90 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H), 4.52 (t,J=4.8 Hz, 2H), 4.35-4.30 (m, 2H), 4.00-3.94 (m, 2H), 3.85 (t, J=11.3 Hz,2H), 3.60-3.55 (m, 2H), 3.50-3.47 (m, 2H), 3.25-3.15 (m, 2H).

Synthesis of (2-(4-(3-(piperidin-1-yl) propoxy) phenyl) thiazol-5-yl)methanamine hydrochloride (375)

Synthesis of tert-butyl ((2-(4-(3-(piperidin-1-yl) propoxy) phenyl)thiazol-5-yl) methyl) carbamate (374)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (200 mg, 0.65 mmol) in diethyl ether (10 mL) underargon atmosphere were added triphenylphosphine (256 mg, 0.98 mmol), DIAD(198 mg, 0.98 mmol) and 3-(piperidin-1-yl) propan-1-ol 373 (112 mg, 0.78mmol) at 0° C.; warmed to RT and stirred for 6 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo to obtain the crude. The crude was purified throughsilica gel column chromatography using 10% MeOH/CH₂Cl₂+5 mL aqueousammonia to afford compound 374 (280 mg, 80%) as an off white solid. TLC:10% MeOH/CH₂Cl₂ (R_(f) 0.2); ¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (d, J=8.8Hz, 2H), 7.60 (s, 1H), 7.53 (t, J=5.0 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H),4.31 (d, J=5.8 Hz, 2H), 4.06 (t, J=6.3 Hz, 2H), 2.45-2.19 (m, 6H),1.95-1.85 (m, 2H), 1.57-1.45 (m, 4H), 1.40 (s, 9H), 1.25-1.11 (m, 2H);LC-MS: 98.75%; 432.1 (M⁺+1); (column; Ascentis Express C-18 (50×3.0 mm,2.7 μm); RT 1.94 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2mL/min).

Synthesis of (2-(4-(3-(piperidin-1-yl) propoxy) phenyl) thiazol-5-yl)methanamine hydrochloride (375)

To a stirring solution of compound 374 (270 mg, 0.62 mmol) in CH₂Cl₂ (5mL) was added 4 N HCl in 1, 4-dioxane (5 mL) under argon atmosphere at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude washed with diethyl ether (5 mL), pentane (5 mL) anddried in vacuo to afford compound 375 (190 mg; 83%) as an off whitesolid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (400 MHz, DMSO-d₆): δ10.20 (br s, 1H), 8.48 (br s, 3H), 7.92-7.84 (m, 3H), 7.08 (d, J=8.9 Hz,2H), 4.32 (q, J=5.5 Hz, 2H), 4.14 (t, J=6.1 Hz, 2H), 3.48-3.43 (m, 2H),3.22-3.13 (m, 2H), 2.94-2.81 (m, 2H), 2.26-2.16 (m, 2H), 1.85-1.67 (m,6H); LC-MS: 99.67%; 332.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0mm, 2.7 μm); RT 1.05 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min).

Synthesis of (2-(4-(3-morpholinopropoxy) phenyl) thiazol-5-yl)methanamine hydrochloride (378)

Synthesis of tert-butyl ((2-(4-(3-morpholinopropoxy)phenyl)thiazol-5-yl)methyl) carbamate (377)

To a stirring solution tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (200 mg, 0.65 mmol) in THF (10 mL) under argonatmosphere were added triphenyl phosphine (342 mg, 1.30 mmol), DIAD (258mg, 1.30 mmol) and 3-morpholinopropan-1-ol 376 (0.13 mL, 0.98 mmol) at0° C.; warmed to RT and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The residue was diluted with water (20 mL) and extracted withEtOAc (3×20 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated to obtain crude. The crude waspurified through silica gel column chromatography using 100% EtOAc toafford compound 377 (250 mg crude) as an off-white solid. TLC: 100%EtOAc (R_(f): 0.2). LC-MS: 66.02%; 434.1 (M⁺+1); (column; AscentisExpress C-18 (50×3.0 mm, 2.7 μm); RT 1.87 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of (2-(4-(3-morpholinopropoxy) phenyl) thiazol-5-yl)methanamine hydrochloride (378)

To a stirring solution of compound 377 (250 mg, 0.57 mmol) in CH₂Cl₂ (5mL) under argon atmosphere was added 4 N HCl in 1, 4-dioxane (4 mL) at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude washed with diethyl ether (20 mL), EtOAc (10 mL) anddried in vacuo to afford compound 378 (125 mg; 83%) as an off whitesolid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (400 MHz, DMSO-d₆): δ9.29 (br s, 1H), 8.98-8.89 (m, 2H), 7.81 (d, J=8.8 Hz, 2H), 7.60 (s,1H), 7.02 (d, J=8.9 Hz, 2H), 4.34-4.30 (m, 2H), 4.11-3.99 (m, 4H),3.60-3.53 (m, 8H), 1.94-1.86 (m, 2H); LC-MS: 96.49%; 334 (M⁺+1);(column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 1.51 min. 2.5 mMAq.NH₄OOCH+5% ACN:CAN+5% 2.5 mM Aq.NH₄OOCH; 1.2 mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N-methyl-N-(2,2, 2-trifluoroethyl) propan-1-amine hydrochloride (383)

Synthesis of tert-butyl ((2-(4-(3-(methylamino) propoxy) phenyl)thiazol-5-yl) methyl) carbamate (380)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (1 g, 3.26 mmol) in dry diethyl ether (50 mL)under argon atmosphere were added triphenyl phosphine (2.56 g, 9.80mmol), 3-(methylamino) propan-1-ol 379 (0.36 mL, 3.92 mmol) anddiisopropyl azodicarboxylate (1.98 g, 9.80 mmol) at 0° C.; warmed to RTand stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(50 mL) and extracted with EtOAc (2×50 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silicagelcolumn chromatography using 15% MeOH/CH₂Cl₂ to afford compound 380 (600mg, 49%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2);LC-MS: 93.67%; 378.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 1.84 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of tert-butyl ((2-(4-(3-(methyl(2, 2, 2-trifluoroethyl) amino)propoxy) phenyl) thiazol-5-yl) methyl) carbamate (382)

To a stirring solution of tert-butyl ((2-(4-(3-(methylamino) propoxy)phenyl) thiazol-5-yl) methyl) carbamate 380 (400 mg, 1.06 mmol) in DMF(8 mL) under inert atmosphere were added triethylamine (0.44 mL, 3.18mmol), 2, 2, 2-trifluoroethyl trifluoromethanesulfonate 381 (0.22 mL,1.59 mmol) at RT and stirred for 4 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (100 mL) and extracted with EtOAc (2×80 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silicagelcolumn chromatography using 5-10% MeOH/CH₂Cl₂ to afford compound 382(200 mg, 41%) as pale yellow liquid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.8).LC-MS: 88.52%; 181.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 0.37 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N-methyl-N-(2,2, 2-trifluoroethyl) propan-1-amine hydrochloride (383)

To a stirring solution of compound 382 (100 mg, 0.21 mmol) in CH₂Cl₂ (2mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (2 mL) at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (2×5mL) and dried in vacuo to afford compound 383 (70 mg, HCl salt) as whitesolid. TLC: 30% EtOAc/hexanes (R_(f): 0.2); LC-MS: 99.39%; 360.0 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.57 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N,N-diethylpropan-1-amine hydrochloride (389)

Synthesis of tert-butyl ((2-(4-(3-hydroxypropoxy) phenyl) thiazol-5-yl)methyl) carbamate (385)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (500 mg, 1.63 mmol) in acetone (10 mL) under inertatmosphere were added potassium carbonate (676 mg, 4.90 mmol),3-bromopropan-1-ol 384 (0.22 mL, 2.45 mmol) and at RT; heated to 60° C.and stirred for 8 h. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was diluted with water (30 mL) andextracted with EtOAc (2×25 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel flash columnchromatography using 50% EtOAc/hexanes to afford compound 385 (400 mg,67%) as an off-white solid. TLC: 60% EtOAc/hexanes (R_(f): 0.2). ¹H NMR(500 MHz, DMSO-d₆): δ 7.81 (d, J=8.7 Hz, 2H), 7.60 (s, 1H), 7.52 (t,J=5.5 Hz, 1H), 7.03 (d, J=9.3 Hz, 2H), 4.55 (t, J=5.2 Hz, 1H), 4.31 (d,J=5.8 Hz, 2H), 4.09 (t, J=6.4 Hz, 2H), 3.61-3.52 (m, 2H), 1.90-1.85 (m,2H), 1.40 (s, 9H); LC-MS: 95.79%; 365.0 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.24 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 3-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenoxy) propyl methanesulfonate (386)

To a stirring solution of compound 385 (300 mg, 0.82 mmol) in CH₂Cl₂ (10mL) under inert atmosphere were added triethylamine (0.23 mL, 1.64mmol), methanesulfonyl chloride (0.07 mL, 0.98 mmol) at 0° C.; warmed toRT and stirred for 3 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(50 mL) and extracted with CH₂Cl₂ (2×50 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to afford crude compound 386 (350 mg, 96%) as pale yellow liquid.TLC: 60% EtOAc/hexanes (R_(f). 0.6); ¹H NMR (400 MHz, DMSO-d₆): δ 7.82(d, J=8.8 Hz, 2H), 7.61 (s, 1H), 7.55-7.46 (m, 1H), 7.06 (d, J=8.9 Hz,2H), 4.37 (t, J=6.3 Hz, 2H), 4.31 (d, J=6.0 Hz, 2H), 4.14 (t, J=6.2 Hz,2H), 3.18 (s, 3H), 2.16 (t, J=6.2 Hz, 2H), 1.40 (s, 9H); LC-MS: 97.12%;443.0 (M⁺+1); (column; Ascentis Express C-18, (50×3.0 mm, 2.7 μm); RT2.50 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-(3-(diethylamino) propoxy) phenyl)thiazol-5-yl) methyl) carbamate (388)

To a stirring solution of compound 386 (350 mg, 0.79 mmol) in THF (5 mL)in a sealed tube under inert atmosphere was added diethylamine 387 (0.41mL, 3.96 mmol) at RT; heated to 70° C. and stirred for 24 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The residue was diluted with water (50mL) and extracted with EtOAc (2×75 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 5-10% MeOH/CH₂Cl₂ to afford compound 388 (220 mg,66%) as pale yellow liquid. TLC: 10% MeOH/CH₂Cl₂ (R_(f). 0.2); ¹H NMR(400 MHz, CD₃OD): δ 7.82 (d, J=8.9 Hz, 2H), 7.59 (s, 1H), 7.02 (d, J=8.9Hz, 2H), 4.41 (s, 2H), 4.11 (t, J=6.0 Hz, 2H), 2.88-2.85 (m, 2H), 2.78(q, J=7.3 Hz, 4H), 2.10-1.97 (m, 2H), 1.46 (s, 9H), 1.15 (t, J=7.2 Hz,6H); LC-MS: 96.43%; 420.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0mm, 2.7 μm); RT 1.94 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N,N-diethylpropan-1-amine dihydrochloride (389)

To a stirring solution of compound 388 (300 mg, 0.71 mmol) in CH₂Cl₂ (5mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (5 mL) at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (2×20mL) and dried in vacuo to afford compound 389 (200 mg, 79%; HCl salt) aswhite solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (400 MHz,DMSO-d₆) δ 10.53 (br s, 1H), 8.58 (br s, 3H), 7.91 (s, 1H), 7.87 (d,J=8.9 Hz, 2H), 7.08 (d, J=8.9 Hz, 2H), 4.32 (q, J=5.5 Hz, 2H), 4.16 (t,J=6.1 Hz, 2H), 3.22-3.04 (m, 6H), 2.20-2.10 (m, 2H), 1.24 (t, J=7.2 Hz,6H); LC-MS: 98.14%; 320.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0mm, 2.7 μm); RT 1.03 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min).

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N,N-dimethylbutan-1-amine hydrochloride (394)

Synthesis of tert-butyl ((2-(4-(4-hydroxybutoxy) phenyl) thiazol-5-yl)methyl) carbamate (391)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (60 mg, 0.19 mmol) in acetone (5 mL) under inertatmosphere were added potassium carbonate (81 mg, 0.58 mmol), TBAI (7.2mg, 0.019 mmol) and 4Chlorobutanol 390 (0.49 mL, 4.90 mmol) at RT;heated to reflux and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was filteredthrough celite and washed with CH₂Cl₂ (40 mL). The filtrate wasconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silicagel flash column chromatography using 50% EtOAc/hexanes;to afford compound 391 (40 mg, 54%) as brown syrup. TLC: 50%EtOAc/hexanes (R_(f): 0.5); LC-MS: 99.31%; 379.1 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.29 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenoxy) butyl methanesulfonate (392)

To a stirring solution of compound 391 (200 mg, 0.52 mmol) in CH₂Cl₂ (5mL) under inert atmosphere were added triethylamine (106 mg, 1.05 mmol),methanesulfonyl chloride (90 mg, 0.79 mmol) at 0° C.; warmed to RT andstirred for 4 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with water (20 mL) andextracted with CH₂Cl₂ (2×20 mL). The combined organic extracts werewashed with saturated sodium bicarbonate solution (30 mL) and water (30mL); dried over sodium sulfate, filtered and concentrated in vacuo toafford crude compound 392 (220 mg, 91%) as brown syrup. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.3); LC-MS: 97.66%; 457.1 (M⁺+1); (column; AscentisExpress C-18, (50×3.0 mm, 2.7 μm); RT 2.56 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of tert-butyl ((2-(4-(4-(dimethylamino) butoxy) phenyl)thiazol-5-yl) methyl) carbamate (393)

To a stirring solution of compound 392 (220 mg, crude 0.48 mmol)) in THF(2 mL) in a sealed tube was added 2 M dimethylamine in THF (3 mL) at RTand heated to 60° C. for 6 h. The reaction was monitored by TLC; aftercompletion the volatiles were removed in vacuo to obtain the crude. Thecrude was either purified through silica gel column chromatography using5% MeOH/CH₂Cl₂ to afford 393 (180 mg, 84%) as brown syrup. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H NMR (400 MHz, DMSO-d₆): δ 7.80 (d, J=8.9Hz, 2H), 7.60 (s, 1H), 7.52 (t, J=5.2 Hz, 1H), 7.02 (d, J=8.9 Hz, 2H),4.31 (d, J=5.8 Hz, 2H), 4.04 (t, J=6.5 Hz, 2H), 2.24 (t, J=7.2 Hz, 2H),2.12 (s, 6H), 1.78-1.68 (m, 2H), 1.58-1.50 (m, 2H), 1.40 (s, 9H); LC-MS:98.90%; 406.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.92 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N,N-dimethylbutan-1-amine hydrochloride (394)

To a stirring solution of compound 393 (230 mg, 0.56 mmol) in CH₂Cl₂ (5mL) was added 4 N HCl in 1, 4-dioxane (6 mL) under argon atmosphere at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude washed with diethyl ether (5 mL) and dried in vacuo toafford 394 (135 mg; 70%) as an off white solid. TLC: 5% MeOH/CH₂Cl₂(R_(f): 0.1); ¹H NMR (400 MHz, DMSO-d₆): δ 10.41 (br s, 1H), 8.54 (br s,3H), 7.95-7.84 (m, 3H), 7.11-7.05 (m, 2H), 4.32 (q, J=5.5 Hz, 2H),4.17-4.09 (m, 2H), 3.14-3.03 (m, 2H), 2.74 (s, 3H), 2.73 (s, 3H),1.89-1.74 (m, 4H);

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N,N-dimethylbutan-1-amine hydrochloride (402)

Synthesis of benzyl (3-oxobutyl) carbamate (397)

To a stirring solution of 4-oxopentanoic acid 395 (3.5 g, 30.15 mmol) inbenzene (50 mL) were added diphenyl phosphonic azide (8.30 g, 30.17mmol) and triethylamine (4.4 mL, 30.17 mmol) at RT; heated to 50° C. for30 min. To this was added benzyl alcohol 396 (4.8 g, 45.26 mmol) andheated to reflux and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The residue was diluted with EtOAc (100 mL),washed with 5% citric acid solution (50 mL), saturated sodiumbicarbonate solution (50 mL), water (50 mL), brine (100 mL). The organicextract was dried over sodium sulfate, filtered and concentrated invacuo to afford the crude. The crude was purified through silica gelcolumn chromatography using 30% EtOAc/hexanes to afford compound 397 (3g, 45%) as pale yellow solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H-NMR(DMSO-d₆, 400 MHz): δ 7.40-7.27 (m, 5H), 7.20 (t, J=5.3 Hz, 1H), 5.00(s, 2H), 3.23-3.17 (m, 2H), 2.60 (t, J=6.8 Hz, 2H), 2.08 (s, 3H); LC-MS:80.94%; 222.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.98 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min);

Synthesis of benzyl (3-hydroxybutyl) carbamate (398)

To a stirring solution of benzyl (3-oxobutyl) carbamate 397 (2 g, 9.05)in MeOH (50 mL) under argon atmosphere was added sodium borohydride (687mg, 18.09 mmol) at 0° C.; warmed to RT and stirred for 4 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with water (50 mL) and extracted with CH₂Cl₂ (2×100mL). The combined organic extracts were dried over sodium sulfate andconcentrated in vacuo to crude compound 398 (1.8 g, 90%) as colorlessliquid. TLC: 30% EtOAc/hexanes (R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz):δ 7.41-7.27 (m, 5H), 7.15 (t, J=4.9 Hz, 1H), 5.00 (s, 2H), 4.41 (d,J=4.6 Hz, 1H), 3.66-3.56 (m, 1H), 3.11-3.00 (m, 2H), 1.49-1.42 (m, 2H),1.04 (d, J=5.8 Hz, 3H); LC-MS: 96.96%; 223.7 (M⁺+1); (column; AscentisExpress C-18, (50×3.0 mm, 2.7 μm); RT 1.99 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of tert-butyl ((2-(4-((4-(((benzyloxy) carbonyl) amino)butan-2-yl) oxy) phenyl) thiazol-5-yl) methyl) carbamate (399)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 398 (2 g, 8.97 mmol) in diethyl ether (50 mL) underargon atmosphere were added triphenylphosphine (7.1 g, 26.91 mmol), DIAD(5.4 g, 26.91 mmol) and benzyl (3-hydroxybutyl) carbamate 356 (2.74 g,8.97 mmol) at RT and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 20-50% EtOAc/hexanes to afford compound 399(1.2 g, crude) as brown color sticky solid. TLC: 50% EtOAc/hexanes(R_(f): 0.4); LC-MS: 67.64%; 512.1 (M⁺+1); (column; Ascentis ExpressC-18 (50×3.0 mm, 2.7 μm); RT 2.87 min. 0.025% Aq.TFA+5% ACN: ACN+5%0.025% Aq TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-((4-aminobutan-2-yl) oxy) phenyl)thiazol-5-yl) methyl) carbamate (400)

To a stirring solution of tert-butyl ((2-(4-((4-(((benzyloxy) carbonyl)amino) butan-2-yl) oxy) phenyl) thiazol-5-yl) methyl) carbamate 399 (600mg, 1.17 mmol) in MeOH (50 mL) under inert atmosphere was added 10% Pd/C(50% wet, 600 mg), ammonium formate (2.95 g, 46.96 mmol) at RT; heatedto reflux and stirred for 24 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was filtered throughcelite washed with 20% MeOH/CH₂Cl₂ (20 mL). The filtrate wasconcentrated in vacuo to obtain the crude. The crude was diluted withEtOAc (100 mL), washed with water (50 mL). The aqueous layer wasextracted with EtOAc (2×50 mL). The combined organic extracts were driedover sodium sulfate and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel (100-200 mesh) columnchromatography using 10% MeOH/CH₂Cl₂ to afford compound 400 (120 mg,30%) as an colorless liquid. TLC: 15% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR(DMSO-d₆, 400 MHz): δ 7.79 (d, J=8.9 Hz, 2H), 7.53 (t, J=5.3 Hz, 1H),7.02 (d, J=8.9 Hz, 2H), 4.70-4.60 (m, 1H), 4.31 (d, J=5.8 Hz, 2H),2.76-2.64 (m, 2H), 1.87-1.75 (m, 1H), 1.72-1.61 (m, 1H), 1.40 (s, 9H),1.26 (d, J=6.1 Hz, 3H); LC-MS: 96.47%; 378.0 (M⁺+1); (column; AscentisExpress C-18 (50×3.0 mm, 2.7 μm); RT 1.90 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-((4-(dimethylamino) butan-2-yl) oxy)phenyl) thiazol-5-yl) methyl) carbamate (401)

To a stirring solution of tert-butyl ((2-(4-((4-aminobutan-2-yl) oxy)phenyl) thiazol-5-yl) methyl) carbamate 400 (180 mg, 0.47 mmol) in MeOH(25 mL) under inert atmosphere were added paraformaldehyde (143 mg, 4.77mmol) and sodium cyanoborohydride (150 mg, 2.39 mmol) portion wise for 5min at 0° C.; warmed to RT and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with EtOAc (100 mL) and washed with water (50 mL), washedwith saturated sodium bicarbonate solution (50 mL). The organic extractwas dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 10% MeOH/CH₂Cl₂ (5% aqueous ammonia) to affordcompound 401 (90 mg, crude) as yellow solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.3); LC-MS: 54.78%; 406.1 (M⁺+1); (column; Ascentis ExpressC-18 (50×3.0 mm, 2.7 μm); RT 1.92 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq TFA, 1.2 mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N,N-dimethylbutan-1-amine hydrochloride (402)

To a stirring solution of tert-butyl ((2-(4-((4-(dimethylamino)butan-2-yl) oxy) phenyl) thiazol-5-yl) methyl) carbamate 401 (90 mg,0.22 mmol) in CH₂Cl₂ (5 mL) was added 4 N HCl in 1, 4-dioxane (0.5 mL)under inert atmosphere at 0° C.; warmed to RT and stirred for 4 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo to afford crude compound 402 (70 mg; HClsalt) as yellow sticky solid. TLC: 50% EtOAc/hexanes (R_(f): 0.1);LC-MS: 79.21%; 306.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 1.03 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N-(2, 2,2-trifluoroethyl) propan-1-amine hydrochloride (406)

Synthesis of tert-butyl ((2-(4-(3-azidopropoxy) phenyl) thiazol-5-yl)methyl) carbamate (403)

To a stirring solution of 4 3-(4-(5-(((tert-butoxycarbonyl) amino)methyl) thiazol-2-yl) phenoxy) propyl methanesulfonate 386 (1 g, 2.26mmol) in DMF (10 mL) under inert atmosphere was added sodium azide (441mg, 6.70 mmol) at 0° C.; warmed to RT and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted water (50 mL) and extracted with EtOAc (2×75 mL).The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude which was triturated withdiethylether (10 mL) and dried in vacuo to afford compound 403 (900 mg,68%) as sticky solid. TLC: 3% MeOH/CH₂Cl₂ (R_(f): 0.8); 41 NMR (DMSO-d₆,500 MHz): δ 7.82 (d, J=8.7 Hz, 2H), 7.61 (s, 1H), 7.53 (t, J=5.5 Hz,1H), 7.05 (d, J=9.3 Hz, 2H), 4.31 (d, J=5.8 Hz, 2H), 4.10 (t, J=6.1 Hz,2H), 3.52 (t, J=6.7 Hz, 2H), 2.03-1.97 (m, 2H), 1.40 (s, 9H); LC-MS:96.94%; 390.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 2.82 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of tert-butyl ((2-(4-(3-aminopropoxy) phenyl) thiazol-5-yl)methyl) carbamate (404)

To a stirring solution of compound 403 (900 mg, crude) in THF:H₂O (4:1,12.5 mL) was added triphenyl phosphine (606 mg, 2.31 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using10% MeOH/CH₂Cl₂ (10 mL aqueous ammonia) to afford compound 404 (530 mg,63%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR(DMSO-d₆, 500 MHz): δ 8.42 (s, 1H), 7.82 (d, J=8.7 Hz, 2H), 7.61 (s,1H), 7.54 (t, J=5.5 Hz, 2H), 7.04 (d, J=8.7 Hz, 2H), 4.31 (d, J=5.8 Hz,2H), 4.11 (t, J=6.4 Hz, 2H), 2.88 (t, J=7.2 Hz, 2H), 1.97 (p, J=6.7 Hz,2H), 1.40 (s, 9H); LC-MS: 99.67%; 364.0 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.84 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-(3-((2, 2, 2-trifluoroethyl) amino)propoxy) phenyl) thiazol-5-yl) methyl) carbamate (405)

To a stirring solution of compound 404 (400 mg, 1.10 mmol) in DMF (5 mL)under inert atmosphere were added triethylamine (0.46 mL, 3.30 mmol), 2,2, 2-trifluoroethyl trifluoromethanesulfonate (0.47 mL, 3.30 mmol) at RTand stirred for 4 h. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was diluted with water (100 mL)and extracted with EtOAc (2×80 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 2% MeOH/CH₂Cl₂ to afford compound 405 (300 mg, 61%)as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.7). LC-MS: 98.65%;446.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT1.98 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)-N-(2, 2,2-trifluoroethyl) propan-1-amine hydrochloride (406)

To a stirring solution of compound 405 (300 mg, 0.67 mmol) in CH₂Cl₂ (5mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (3 mL) at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (2×10mL) and dried in vacuo to afford compound 406 (230 mg, 89%; HCl salt) asbrown solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (400 MHz,DMSO-d₆): δ 10.15 (br, 2H), 8.56 (br s, 3H), 7.94-7.81 (m, 3H), 7.07 (d,J=8.9 Hz, 2H), 4.92 (s, 2H), 4.32 (q, J=5.4 Hz, 2H), 4.21-4.08 (m, 2H),3.21 (t, J=7.5 Hz, 2H), 2.27-2.18 (m, 2H); LC-MS: 98.51%; 346.0 (M⁺+1);(column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 1.97 min. 2.5 mM Aq.NH₄OOCH: 5% ACN; 0.8 mL/min).

Synthesis of N-(3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propyl)acetamide hydrochloride (408)

Synthesis of tert-butyl ((2-(4-(3-acetamidopropoxy) phenyl)thiazol-5-yl) methyl) carbamate (407)

To a stirring solution of tert-butyl ((2-(4-(3-aminopropoxy) phenyl)thiazol-5-yl) methyl) carbamate 404 (250 mg, 0.68 mmol) in CH₂Cl₂ (20mL) under inert atmosphere were added triethylamine (0.25 mL, 1.70mmol), acetylchloride (0.053 mL, 0.75 mmol) at 0° C.; warmed to RT andstirred for 3 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with CH₂Cl₂ (100 mL),washed with water (75 mL). The organic extract was dried over sodiumsulfate, filtered and concentrated in vacuo to afford crude which wastriturated with 10% EtOAc/hexanes (10 mL), diethylether (5 mL) and driedin vacuo to afford compound 407 (220 mg, 79%) as colorless liquid. TLC:10% MeOH/CH₂Cl₂ (R_(f): 0.6); ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.11-8.02 (m,0.6H), 7.90 (t, J=4.6 Hz, 0.4H), 7.81 (d, J=8.7 Hz, 2H), 7.61 (s, 1H),7.53 (t, J=5.5 Hz, 1H), 7.03 (dd, J=9.0, 2.6 Hz, 2H), 4.31 (d, J=5.8 Hz,2H), 4.08-4.00 (m, 2H), 3.28-3.16 (m, 2H), 1.91-1.82 (m, 3.5H), 1.80 (s,1.5H), 1.40 (s, 9H); LC-MS: 98.81%; 406.1 (M⁺+1); (column; AscentisExpress C-18, (50×3.0 mm, 2.7 μm); RT 2.18 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of N-(3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propyl)acetamide hydrochloride (408)

To a stirring solution of compound 407 (210 mg, 0.48 mmol) in CH₂Cl₂ (5mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (3 mL) at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (2×50mL), n-hexane (25 mL) and dried in vacuo to afford compound 408 (160 mg,91%; HCl salt) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2);¹H-NMR (DMSO-d₆, 500 MHz): δ 8.52 (br s, 3H), 7.90 (s, 1H), 7.86 (d,J=8.7 Hz, 2H), 7.06 (dd, J=8.7, 2.9 Hz, 2H), 4.32 (q, J=5.8 Hz, 2H),4.06 (q, J=5.8 Hz, 2H), 3.29-3.14 (m, 2H), 1.92-1.83 (m, 2H), 1.80 (s,3H);

Synthesis of 2, 2′-((3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)propyl) azanediyl) bis (ethan-1-ol) hydrochloride (411)

Synthesis of tert-butyl ((2-(4-(3-(bis(2-hydroxyethyl) amino) propoxy)phenyl) thiazol-5-yl) methyl) carbamate (410)

To a stirring solution of compound 386 (1.7 g, 3.84 mmol) in DMF (30 mL)under inert atmosphere were added 2,2′-azanediylbis(ethan-1-ol) 409 (807mg, 7.69 mmol) and potassium carbonate (1.6 g, 11.52 mmol) at RT; heatedto 100° C. and stirred for 24 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted with10% MeOH/CH₂Cl₂ and washed with water. The organic extract was driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel column chromatographyusing 10% MeOH/CH₂Cl₂ to afford compound 410 (400 mg, 23%) as stickysolid. TLC:MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H NMR (500 MHz, DMSO-d₆): δ 7.80(d, J=8.7 Hz, 2H), 7.59 (s, 1H), 7.52 (br t, J=5.5 Hz, 1H), 7.02 (d,J=8.7 Hz, 2H), 4.54 (t, J=4.9 Hz, 1H), 4.30 (d, J=5.8 Hz, 2H), 4.08 (t,J=6.4 Hz, 2H), 3.55 (q, J=5.8 Hz, 2H), 1.89-1.84 (m, 2H), 1.39 (s, 9H);LC-MS: 89.41%; 452.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 1.80 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 2, 2′-((3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)propyl) azanediyl) bis (ethan-1-ol) hydrochloride (411)

To a stirring solution of compound 410 (400 mg, 0.88 mmol) in CH₂Cl₂ (10mL) was added 4 N HCl in 1, 4-dioxane (2 mL) under argon atmosphere at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was triturated with isopropanol (3 mL), EtOAc (7 mL)and dried in vacuo to afford compound 411 (350 mg crude, HCl salt) as anoff white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H NMR (400 MHz,DMSO-d₆): δ 11.53 (s, 1H), 9.49 (t, J=5.7 Hz, 1H), 8.92-8.83 (m, 1H),8.75-8.63 (m, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.01-7.96 (m, 2H), 7.92-7.80(m, 6H), 7.73 (s, 1H), 7.03 (d, J=8.9 Hz, 2H), 4.66 (d, J=5.5 Hz, 2H),4.04-3.89 (m, 2H), 3.38-3.32 (m, 1H), 3.28-3.20 (m, 1H), 2.85-2.71 (m,2H), 2.28-2.18 (m, 1H), 1.89-1.79 (m, 2H), 1.73-1.63 (m, 1H), 1.41-1.28(m, 1H);

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl)phenoxy)-N-isopropyl-N-methylpropan-1-amine hydrochloride (414)

Synthesis of tert-butyl ((2-(4-(3-(isopropyl (methyl) amino) propoxy)phenyl) thiazol-5-yl) methyl) carbamate (413)

To a stirring solution of 3-(4-(5-(((tert-butoxy carbonyl) amino)methyl) thiazol-2-yl) phenoxy) propyl methanesulfonate 356 (1.3 g, 2.94mmol) in DMF (20 mL) under inert atmosphere were added potassiumcarbonate (1.22 g, 8.82 mmol), N-methylpropan-2-amine 412 (430 mg, 5.89mmol) at RT and stirred for 48 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withEtOAc (2×75 mL), washed with water (50 mL). The organic extract wasdried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel flash columnchromatography using 6% EtOAc/hexanes to afford compound 413 (300 mg,32%) as an off-white solid. TLC: 5% MeOH/CH2Cl2 (R_(f): 0.4). LC-MS:96.38%; 420.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7nm); RT 1.92 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl)phenoxy)-N-isopropyl-N-methylpropan-1-amine hydrochloride (414)

To a stirring solution of compound 413 (300 mg, 0.71 mmol) in CH₂Cl₂ (10mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (1 mL) at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (2×10mL) and dried in vacuo to afford compound 414 (260 mg, HCl salt) as anoff-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400MHz): 10.41 (br s, 1H), 8.54 (br s, 3H), 7.92-7.85 (m, 3H), 7.08 (d,J=8.7 Hz, 2H), 4.32 (q, J=5.8 Hz, 2H), 4.15 (t, J=6.1 Hz, 2H), 3.58-3.54(m, 2H), 3.29-3.21 (m, 1H), 3.14-3.05 (m, 1H), 2.29-2.14 (m, 2H), 1.28(d, J=7.0 Hz, 3H), 1.23 (d, J=6.4 Hz, 3H); Mass: 320.1 (M⁺+1);

Synthesis of N-(3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)propyl)-N-methylcyclopropanamine hydrochloride (417)

Synthesis of tert-butyl ((2-(4-(3-(cyclopropyl (methyl) amino) propoxy)phenyl) thiazol-5-yl) methyl) carbamate (416)

To a stirring solution of 3-(4-(5-(((tert-butoxy carbonyl) amino)methyl) thiazol-2-yl) phenoxy) propyl methanesulfonate 356 (1.0 g, 2.26mmol) in DMF (10 mL) under inert atmosphere were added potassiumcarbonate (935 mg, 13.57 mmol), N-methylcyclopropanamine 415 (963 mg,13.57 mmol) at 0° C.; heated to 70° C. and stirred for 24 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with EtOAc (2×75 mL), washed with water (50mL). The organic extract was dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel flash column chromatography using 5% MeOH/CH₂Cl₂ toafford compound 416 (180 mg, 19%) as sticky solid. TLC: 5% MeOH/CH₂Cl₂(R_(f). 0.4). LC-MS: 96.38%; 418.1 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 1.94 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min). ¹H-NMR (DMSO-d₆, 400 MHz): δ 7.80 (d, J=8.7Hz, 2H), 7.60 (s, 1H), 7.53 (d, J=5.8 Hz, 1H), 7.02 (d, J=8.7 Hz, 2H),4.31 (d, J=5.8 Hz, 2H), 4.02 (t, J=6.4 Hz, 2H), 2.62 (t, J=7.0 Hz, 2H),2.26 (s, 3H), 1.88 (p, J=6.8 Hz, 2H), 1.65-1.60 (m, 1H), 1.40 (s, 9H),0.45-0.38 (m, 2H), 0.29-0.24 (m, 2H);

Synthesis of N-(3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)propyl)-N-methylcyclopropanamine hydrochloride (417)

To a stirring solution of compound 416 (180 mg, 0.43 mmol) in CH₂Cl₂ (5mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (0.5 mL) at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (2×10mL) and dried in vacuo to afford compound 417 (160 mg, HCl salt) assticky solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 500MHz): 11.00 (br s, 1H), 8.65 (br s, 3H), 7.91 (s, 1H), 7.87 (d, J=8.7Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 4.31 (q, J=5.8 Hz, 2H), 4.16 (t, J=6.1Hz, 2H), 3.40-3.26 (m, 2H), 2.90-2.84 (m, 1H), 2.82 (d, J=4.6 Hz, 3H),2.35-2.19 (m, 2H), 1.25-1.04 (m, 2H), 0.94-0.73 (m, 2H); LC-MS (AgilentIon Trap): 90.32%; 318.3 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm,2.6 um); RT 2.72 min. 2.5 mM Aq. NH₄OAc:ACN; 0.8 mL/min).

Synthesis of tert-butyl ((2-(4-((4-(diethylamino) butan-2-yl) oxy)phenyl) thiazol-5-yl) methyl) carbamate (419)

Synthesis of tert-butyl ((2-(4-((4-(diethylamino) butan-2-yl) oxy)phenyl) thiazol-5-yl) methyl) carbamate (418)

To a stirring solution of tert-butyl ((2-(4-((4-aminobutan-2-yl) oxy)phenyl) thiazol-5-yl) methyl) carbamate 400 (200 mg, 0.53 mmol) in MeOH(20 mL) under inert atmosphere were added acetaldehyde (116 mg, 2.65mmol), acetic acid (0.05 mL) and sodium cyanoborohydride (167 mg, 2.65mmol) at 0° C.; warmed to RT and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The residue was diluted with water (100 mL) andextracted with EtOAc (2×50 mL). The combined organic extracts werewashed with brine, dried over sodium sulfate, filtered and concentratedin vacuo to afford compound 418 (200 mg, 87%) as colorless syrup. TLC:10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 7.82 (d,J=8.8 Hz, 2H), 7.61 (s, 1H), 7.53 (t, J=5.8 Hz, 1H), 7.04 (d, J=8.9 Hz,2H), 4.74-4.50 (m, 1H), 4.31 (d, J=5.9 Hz, 2H), 3.14-2.93 (m, 6H),1.41-1.38 (m, 11H), 1.30 (d, J=6.1 Hz, 3H), 1.17 (t, J=7.1 Hz, 6H);LC-MS: 87.75%; 434.1 (M⁺+1); (column; Ascentis Express C-18 (50×3.0 mm,2.7 μm); RT 2.03 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2mL/min).

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl)phenoxy)-N,N-diethylbutan-1-amine hydrochloride (419)

To a stirring solution of tert-butyl ((2-(4-((4-(diethylamino)butan-2-yl) oxy) phenyl) thiazol-5-yl) methyl) carbamate 418 (200 mg,0.46 mmol) in CH₂Cl₂ (20 mL) was added 4 N HCl in 1, 4-dioxane (2 mL)under inert atmosphere at 0° C.; warmed to RT and stirred for 4 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo to afford crude compound 419 (200 mg) asyellow sticky solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.1); LC-MS: 89.46%;334.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT1.00 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 1-(((2-(4-(3-(azetidin-1-yl) propoxy) phenyl) thiazol-5-yl)methyl)-14-azanyl)-2, 2, 2-trifluoroethan-1-one (422)

Synthesis of tert-butyl ((2-(4-(3-(azetidin-1-yl) propoxy) phenyl)thiazol-5-yl) methyl) carbamate (421)

To a stirring solution of compound 386 (1 g, 2.47 mmol) in DMF (30 mL)were added potassium carbonate (1.7 g, 12.37 mmol) and azetidine 420(705 mg, 12.37 mmol) at RT under inert atmosphere. The reaction mixturewas heated to 80° C. and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith water (30 mL) and extracted with EtOAc (2×30 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 10% MeOH/CH₂Cl₂ to affordcrude compound 421 (130 mg) as yellow syrup. ¹H NMR (400 MHz, DMSO-d₆):δ 7.79 (d, J=8.9 Hz, 2H), 7.59 (s, 1H), 7.54-7.48 (m, 1H), 7.00 (d,J=8.8 Hz, 2H), 4.29 (d, J=5.9 Hz, 2H), 4.04-3.97 (m, 2H), 3.08-3.05 (m,4H), 2.47-2.42 (m, 2H), 1.96-1.90 (m, 2H), 1.69-1.67 (m, 2H), 1.38 (s,9H); LC-MS: 70.31%; 404.1 (M⁺+1) (column; Ascentis Express C-18, (50×3.0mm, 2.7 μm); RT 1.89 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min).

Synthesis of 1-(((2-(4-(3-(azetidin-1-yl) propoxy) phenyl) thiazol-5-yl)methyl)-14-azanyl)-2, 2, 2-trifluoroethan-1-one (422)

To a stirring solution of compound 421 (130 mg, 0.29 mmol) in CH₂Cl₂ (10mL) was added trifluoroacetic acid (0.06 mL, 0.87 mmol) at 0° C. underinert atmosphere. The reaction mixture was gradually warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo to afford crudecompound 422 (100 mg) as an off-white solid. This crude material wastaken to next step without further purification. TLC: 70% EtOAc/Hexane(R_(f). 0.1); LC-MS: 24.00%; 304.1 (M⁺+1); (column; Kinetex EVO C-18(50×3.0 mm, 2.6 um); RT 1.07 min. 2.5 mM NH₄OOCH in water+5% ACN: ACN+5%2.5 mM NH₄OOCH in water, 0.8 mL/min).

Synthesis of 1-(1-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl)cyclopropyl)-N, N-dimethylmethanamine hydrochloride (431)

Synthesis of ethyl 1-cyanocyclopropane-1-carboxylate (425)

To a stirring solution of ethyl 2-cyanoacetate 423 (5 g, 44.20 mmol) inacetone (100 mL) were added potassium carbonate (18.3 g, 132.60 mmol)and 1,2-dibromo ethane (8 mL, 88.4 mmol) 424 at RT under inertatmosphere. The reaction mixture was heated to 70° C. and stirred for 16h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was filtered through celite and washed with acetone(200 mL). The filtrate was dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the compound 425 (10 g, crude) as brownliquid. ¹H NMR (400 MHz, CDCl₃): δ 4.27 (q, J=7.2 Hz, 2H), 1.68 (t,J=3.5 Hz, 2H), 1.68 (t, J=3.5 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H)

Synthesis of 1-(hydroxymethyl) cyclopropane-1-carbonitrile (426)

To a stirring solution of compound 425 (4 g, 28.78 mmol) in 1,2-dimethoxy ethane:MeOH (9:1, 88 mL) was added sodium borohydride (8.7g, 228.90 mmol) at RT under inert atmosphere. The reaction mixture wasstirred at RT for 48 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withsaturated sodium bicarbonate solution (50 mL) and extracted with 10%MeOH/CH₂Cl₂ (2×50 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to afford compound426 (1.4 g, 54%) as yellow color liquid. ¹H NMR (400 MHz, CDCl₃): δ 4.25(br s, 1H), 3.63 (s, 2H), 1.32-1.24 (m, 2H), 1.02-0.92 (m, 2H)

Synthesis of 1-(hydroxymethyl) cyclopropane-1-carbonitrile (427)

To a stirring solution of compound 426 (1 g, 10.31 mmol) in CH₂Cl₂ (20mL) under inert atmosphere were added triethyl amine (4.5 mL, 30.93mmol), methane sulfonyl chloride (1.68 mL, 20.62 mmol) at 0° C.; stirredRT for 2 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was quenched with water (20 mL) andextracted with CH₂Cl₂ (2×20 mL). The combined organic extracts werewashed with sodium bicarbonate solution (20 mL), brine (20 mL) driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude compound 427 (1.5 g) as brown liquid. TLC: 30% EtOAc/Hexane(R_(f): 0.5); ¹H NMR (400 MHz, CDCl₃): δ 4.19 (s, 2H), 3.15 (s, 3H),1.49-1.44 (m, 2H), 1.21-1.16 (m, 2H)

Synthesis of tert-butyl ((2-(4-((1-cyanocyclopropyl) methoxy) phenyl)thiazol-5-yl) methyl) carbamate (428)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (500 mg, 1.64 mmol) in DMF (10 mL) were addedcompound 427 (858 mg, 4.90 mmol) and potassium carbonate (1.13 g, 5.0mmol) at RT under inert atmosphere. The reaction mixture was heated to70° C. and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was mixture was dilutedwith ice cold water (20 mL) and extracted with EtOAc (2×20 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough column chromatography using 2-5% MeOH/CH₂Cl₂ to afford compound428 (500 mg, 79%) as colorless liquid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.6);¹H NMR (500 MHz, DMSO-d₆): δ 7.83 (d, J=8.7 Hz, 2H), 7.62 (s, 1H),7.54-7.52 (m, 1H), 7.06 (d, J=8.7 Hz, 2H), 4.31 (d, J=5.8 Hz, 2H), 4.10(s, 2H), 1.40 (s, 9H), 1.21-1.12 (m, 4H); LC-MS: 85.37%; 386.1 (M⁺+1)(column; Ascentis Express C-18, (50×3.0 mm, 2.7 μm); RT 0.58 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of tert-butyl ((2-(4-((1-(aminomethyl) cyclopropyl) methoxy)phenyl) thiazol-5-yl) methyl) carbamate (429)

To a stirring solution of compound 428 (400 mg, 1.04 mmol) in a mixtureof methanol and ammonia (9:1, 50 mL) was added Raney Ni (100 mg) at RTunder inert atmosphere. The reaction mixture was stirred under hydrogenatmosphere (balloon pressure) at RT for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasfiltered through a pad of celite and the celite bed was washed with 10%MeOH/CH₂Cl₂ (50 mL). The filtrate was concentrated in vacuo to obtainthe crude. The crude was purified through neutral alumina columnchromatography using 10% MeOH/CH₂Cl₂ to afford compound 429 (250 mg,62%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR(500 MHz, DMSO-d₆): δ 8.01-7.91 (m, 1H), 7.82 (d, J=8.7 Hz, 2H), 7.60(s, 1H), 7.57-7.55 (m, 1H), 7.03 (d, J=8.7 Hz, 2H), 4.29 (d, J=5.8 Hz,2H), 4.11-4.03 (m, 1H), 3.97 (s, 2H), 2.91 (s, 2H), 1.38 (s, 9H),0.79-0.72 (m, 2H), 0.70-0.64 (m, 2H); LC-MS: 89.88%; 390.1 (M⁺+1);(column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 2.33 min. 2.5 mMNH₄OOCH in water+5% ACN: ACN+5% 2.5 mM NH₄OOCH in water, 0.8 mL/min).

Synthesis of tert-butyl ((2-(4-((1-((dimethylamino) methyl) cyclopropyl)methoxy) phenyl) thiazol-5-yl) methyl) carbamate (430)

To a stirring solution of compound 429 (250 mg, 0.64 mmol) in methanol(25 mL) were added paraformaldehyde (96 mg, 3.21 mmol) and sodiumcyanoborohydride (202 mg, 3.21 mmol) at 0° C. under inert atmosphere.The reaction mixture was gradually warmed to RT and stirred for 16 h.The reaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The residue was dilute with saturatedsodium bicarbonate solution (20 mL) and extracted with EtOAc (2×30 mL).The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude was purifiedthrough column chromatography using 2-5% MeOH/CH₂Cl₂ to afford compound430 (160 mg, 59%) as an off white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f):0.5); LC-MS: 84.53%; 418.1 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm,2.6 um); RT 2.55 min. 2.5 mM NH₄OOCH in water+5% ACN: ACN+5% 2.5 mMNH₄OOCH in water, 0.8 mL/min).

1-(1-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl) cyclopropyl)-N,N-dimethylmethanamine hydrochloride (431)

To a stirring solution of compound 430 (160 mg, 0.38 mmol) in CH₂Cl₂ (20mL) was added 4 N HCl in 1, 4-dioxane (2 mL) under argon atmosphere at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude washed with ether (20 mL) to afford compound 431 (150mg, HCl salt) as an off-white solid. TLC: 40% EtOAc/Hexane (R_(f): 0.1);¹H NMR (400 MHz, DMSO-d₆): δ), 8.60 (br s, 3H), 7.90 (s, 1H), 7.87 (d,J=8.8 Hz, 2H), 7.06 (d, J=8.9 Hz, 2H), 4.35-4.29 (m, 2H), 4.04 (s, 2H),3.26-3.18 (m, 2H), 2.82 (d, J=4.9 Hz, 6H), 0.82 (s, 4H); LC-MS: 94.00%;318.3 (M⁺+1) (des-Boc); (column; Cortecs C18, (50×3.0 mm, 2.7 μm); RT3.05 min. 2.5 mM Aq NH₄HCO₃:ACN, 0.8 mL/min);

Synthesis of 1-(1-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl)cyclobutyl)-N, N-dimethylmethanamine hydrochloride (439)

Synthesis of ethyl 1-cyanocyclobutane-1-carboxylate (433)

To a stirring solution of ethyl 2-cyanoacetate 423 (7 g, 61.95 mmol) inacetone (300 mL) were added 1,3-dibromopropane 432 (9.47 mL, 92.92 mmol)and potassium carbonate (25.6 g, 185.84 mmol) at RT under inertatmosphere. The reaction mixture was heated to 70-80° C. and stirred for16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was filtered through a pad of celite andthe celite bed was washed with EtOAc (100 mL). The filtrate wasconcentrated in vacuo to afford compound 433 (10 g) as pale yellowliquid. This crude material was taken to next step without furtherpurification. TLC: 30% EtOAc/hexanes (R_(f): 0.5).

Synthesis of 1-(hydroxymethyl) cyclobutane-1-carbonitrile (434)

To a stirring solution of compound 433 (5 g, crude) in a mixture ofDME/MeOH (10:1, 110 mL) was added sodium borohydride (10 g, 261.44 mmol)portion wise at 0° C. under inert atmosphere. The reaction mixture wasgradually warmed to RT and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasquenched slowly with aqueous sodium bicarbonate solution (50 mL) andextracted with 10% MeOH/CH₂Cl₂ (2×50 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toafford compound 434 (2 g) as pale yellow liquid. This crude material wastaken to next step without further purification. TLC: 30% EtOAc/hexanes(R_(f): 0.3).

Synthesis of (1-cyanocyclobutyl) methyl methanesulfonate (435)

To a stirring solution of compound 434 (500 mg, crude) in CH₂Cl₂ (10 mL)were added methanesulfonyl chloride (0.4 mL, 5.4 mmol) and triethylamine(0.94 mL, 6.75 mmol) at 0° C. under inert atmosphere. The reactionmixture was gradually warmed to RT and stirred for 3 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas poured into aqueous sodium bicarbonate solution (30 mL) andextracted with EtOAc (2×30 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to affordcompound 435 (600 mg) as pale yellow liquid. This crude material wastaken to next step without further purification. TLC: 30% EtOAc/hexanes(R_(f): 0.4).

Synthesis of tert-butyl ((2-(4-((1-cyanocyclobutyl) methoxy) phenyl)thiazol-5-yl) methyl) carbamate (436)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (1.5 g, 4.9 mmol) in DMF (40 mL) were addedcompound 435 (3.24 g, 17.16 mmol) and potassium carbonate (2.03 g, 14.7mmol) at RT under inert atmosphere. The reaction mixture was heated to80° C. and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was mixture was dilutedwith ice cold water (30 mL) and extracted with EtOAc (2×40 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough column chromatography using 3% MeOH/CH₂Cl₂ to afford compound436 (1.2 g, 61%) as an off white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f):0.7); LC-MS: 87.97%; 400.1 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm,2.6 um); RT 3.38 min. 2.5 mM NH₄OOCH in water+5% ACN: ACN+5% 2.5 mMNH₄OOCH in water, 0.8 mL/min).

Synthesis of tert-butyl ((2-(4-((1-(aminomethyl) cyclobutyl) methoxy)phenyl) thiazol-5-yl) methyl) carbamate (437)

To a stirring solution of compound 436 (900 mg, 2.25 mmol) in a mixtureof methanol and ammonia (10:1, 66 mL) was added Raney Ni (200 mg) at RTunder inert atmosphere. The reaction mixture was stirred under hydrogenatmosphere (balloon pressure) at RT for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasfiltered through a pad of celite and the celite bed was washed with 10%MeOH/CH₂Cl₂ (50 mL). The filtrate was concentrated in vacuo to affordcompound 437 (800 mg) as pale yellow sticky syrup. This crude materialwas taken to next step without further purification. TLC: 5% MeOH/CH₂Cl₂(R_(f): 0.2); ¹H NMR (500 MHz, DMSO-d₆): δ 7.96 (s, 1H), 7.84-7.81 (m,2H), 7.53 (br s, 1H), 7.10-7.06 (m, 2H), 4.30 (d, J=4.6 Hz, 2H),3.32-3.22 (m, 2H), 2.43-2.31 (m, 2H), 2.08-1.79 (m, 6H), 1.39 (s, 9H);LC-MS: 78.30%; 404.2 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 2.03 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of tert-butyl ((2-(4-((1-((dimethylamino) methyl) cyclobutyl)methoxy) phenyl) thiazol-5-yl) methyl) carbamate (438)

To a stirring solution of compound 437 (800 mg, crude) in methanol (30mL) were added paraformaldehyde (297 mg, 9.92 mmol) and sodiumcyanoborohydride (615 mg, 9.92 mmol) at 0° C. under inert atmosphere.The reaction mixture was gradually warmed to RT and stirred for 16 h.The reaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The residue was dilute with water (30mL) and extracted with EtOAc (2×40 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through column chromatographyusing 8% MeOH/CH₂Cl₂ to afford compound 438 (560 mg, 65%) as an offwhite solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H NMR (500 MHz,DMSO-d₆): δ 7.83 (d, J=8.7 Hz, 2H), 7.61 (s, 1H), 7.53 (t, J=5.2 Hz,1H), 7.08 (d, J=8.1 Hz, 2H), 4.31 (d, J=5.8 Hz, 2H), 4.16-4.05 (m, 2H),3.17 (d, J=5.2 Hz, 2H), 2.33-2.07 (m, 4H), 2.05-1.77 (m, 8H), 1.40 (s,9H); LC-MS: 97.54%; 432.2 (M⁺+1); (column; Ascentis Express C18, (50×3.0mm, 2.7 μm); RT 2.00 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min).

Synthesis of 1-(1-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl)cyclobutyl)-N, N-dimethylmethanamine hydrochloride (439)

To a stirring solution of compound 438 (560 mg, 1.3 mmol) in CH₂Cl₂ (13mL) was added 4 N HCl in 1, 4-dioxane (3 mL) at 0° C. under inertatmosphere. The reaction mixture was gradually warmed to RT and stirredfor 2 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo to obtain the crude. Thecrude was triturated with EtOAc (20 mL), diethylether (20 mL) and driedin vacuo to afford compound 439 (450 mg, HCl salt) as an off whitesolid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H NMR (500 MHz, DMSO-d₆): δ8.65 (br s, 3H), 7.94-7.86 (m, 3H), 7.15 (d, J=8.7 Hz, 2H), 4.31 (q,J=5.2 Hz, 2H), 4.27 (s, 2H), 3.35 (d, J=5.8 Hz, 2H), 2.78 (s, 3H), 2.77(s, 3H), 2.14-1.88 (m, 6H); LC-MS: 98.70%; 332.1 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.39 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 1-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl)cyclobutane-1-carbonitrile hydrochloride (440)

Synthesis of 1-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy) methyl)cyclobutane-1-carbonitrile hydrochloride (440)

To a stirring solution of compound 436 (300 mg, 0.75 mmol) in CH2Cl2 (10mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under argon atmosphere at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude washed with diethyl ether (10 mL), EtOAc (10 mL) anddried in vacuo to afford compound 440 (150 mg; HCl salt) as pale yellowsolid. TLC: 5% MeOH/CH2Cl2 (R_(f): 0.1); 1H NMR (400 MHz, DMSO-d6): δ8.60 (br s, 3H), 7.92 (s, 1H), 7.89 (d, J=8.9 Hz, 2H), 7.14 (d, J=8.9Hz, 2H), 4.34 (s, 2H), 4.32 (d, J=5.6 Hz, 2H), 2.56-2.50 (m, 2H),2.33-2.19 (m, 2H), 2.17-2.07 (m, 2H); LC-MS: 98.63%; 299.9 (M++1);(column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 2.05 min. 2.5 mMNH4OOCH in water+5% ACN: ACN+5% 2.5 mM NH4OOCH in water, 0.8 mL/min).

Synthesis of 4-(1-(5-(aminomethyl) thiazol-2-yl)-1H-pyrazol-4-yl)-N,N-dimethylbutan-1-amine hydrochloride (448) and4-(1-(5-(aminomethyl)thiazol-2-yl)-1H-pyrazol-4-yl)-N,N-diethylbutan-1-amine hydrochloride (448A)

Synthesis of tert-butyl ((2-(4-bromo-1H-pyrazol-1-yl) thiazol-5-yl)methyl) carbamate (442)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (10 g, 40.32 mmol) in DMF (100 mL) under inert atmospherewere added 4-bromo-1H-pyrazole 441 (5.92 g, 40.29 mmol), cesiumcarbonate (39.4 g, 120.96 mmol) at RT; heated to 80° C. and stirred for16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with ice-cold water (500 mL)and extracted with EtOAc (2×200 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silicagel columnchromatography using 30% EtOAc/hexanes to afford compound 442 (4.1 g,29%) as an off-white solid. TLC: 30% EtOAc/hexanes (R_(f): 0.3). ¹H-NMR(DMSO-d₆, 500 MHz): δ 8.74 (s, 1H), 7.99 (s, 1H), 7.57 (t, J=5.2 Hz,1H), 7.46 (s, 1H), 4.27 (d, J=6.4 Hz, 2H), 1.40 (s, 9H); LC-MS: 83.58%;359.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT2.69 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl 42-(4-(4-hydroxybut-1-yn-1-yl)-1H-pyrazol-1-yl)thiazol-5-yl) methyl) carbamate (444)

To a stirring solution of compound 442 (4.1 g, 11.45 mmol) intriethylamine (50 mL) were added but-3-yn-1-ol 443 (1.2 g, 17.18 mmol),Copper(I) iodide (22 mg, 0.11 mmol) and purged under argon atmospherefor 20 min. To this was added Pd(PPh₃)₂Cl₂ (160 mg, 0.22 mmol) andpurged under argon atmosphere for 10 min; heated to 80° C. and stirredfor 2 h. The reaction was monitored by TLC; after completion thereaction mixture was diluted with water (75 mL) and extracted with EtOAC(2×100 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 40%EtOAc/hexanes to afford compound 444 (2.7 g, crude) as an off-whitesolid. TLC: 50% EtOAc/hexanes (R_(f): 0.4); LC-MS: 62.79%; 349.0 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.25 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-(4-hydroxybutyl)-1H-pyrazol-1-yl)thiazol-5-yl) methyl) carbamate (445)

To a stirring solution of compound 444 (2.7 g, 7.75 mmol) in MeOH (30mL) under inert atmosphere was added 10% Pd/C (800 mg, 50% w/w) at RTand stirred under hydrogen atmosphere (balloon pressure) at RT for 16 h.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite and eluted with 10%MeOH/CH₂Cl₂ (100 mL). The filtrate was concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 50% EtOAc/hexanes to afford compound 445 (1.8 g,67%) as colorless thick syrup. TLC: 50% EtOAc/hexanes (R_(f): 0.6); ¹HNMR (DMSO-d₆, 500 MHz): δ 8.22 (s, 1H), 7.69 (s, 1H), 7.57-7.51 (m, 1H),7.39 (s, 1H), 4.36 (t, J=4.9 Hz, 1H), 4.25 (d, J=5.8 Hz, 2H), 3.39-3.34(m, 2H), 2.49-2.46 (m, 2H), 1.63-1.54 (m, 2H), 1.49-1.43 (m, 2H), 1.40(s, 9H); LC-MS: 99.7\5%; 353.1 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 2.19 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min).

Synthesis of 4-(1-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl)-1H-pyrazol-4-yl) butyl methanesulfonate (446)

To a stirring solution of compound 445 (1.8 g, 5.11 mmol) in CH₂Cl₂ (20mL) under inert atmosphere were added triethylamine (1.5 mL, 10.22mmol), methanesulfonyl chloride (0.62 mL, 7.67 mmol) at 0° C.; warmed toRT and stirred for 4 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(75 mL) extracted with CH₂Cl₂ (2×25 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toafford crude. The crude was purified through silica gel columnchromatography using 50% EtOAc/hexanes to afford crude compound 446 (2g) as an off-white solid. TLC: 50% EtOAc/to hexanes (R_(f): 0.6); ¹H NMR(DMSO-d₆, 500 MHz): δ 8.27 (s, 1H), 7.71 (s, 1H), 7.58-7.51 (m, 1H),7.39 (s, 1H), 4.27-4.20 (m, 4H), 3.15 (s, 3H), 2.56-2.51 (m, 2H),1.73-1.61 (m, 4H), 1.40 (s, 9H); LC-MS: 95.12%; 431.1 (M⁺+1); (column;Ascentis Express C-18, (50×3.0 mm, 2.7 μm); RT 2.53 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-(4-(dimethylamino)butyl)-1H-pyrazol-1-yl) thiazol-5-yl) methyl) carbamate (447)

To a stirring solution of compound 446 (1.4 g, 3.25 mmol) in THF (10 mL)in a sealed tube under inert atmosphere was added dimethylamine (5 mL)at RT; heated to 80° C. and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo. The crude was purified through silica gel column chromatographyusing 5% MeOH/CH₂Cl₂ to afford compound 447 (220 mg, 69%) as brownsyrup. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (DMSO-d₆, 500 MHz): δ8.23 (s, 1H), 7.69 (s, 1H), 7.58-7.52 (m, 1H), 7.39 (s, 1H), 4.25 (d,J=5.8 Hz, 2H), 2.76-2.71 (m, 2H), 2.51-2.44 (m, 2H), 2.21 (t, J=7.2 Hz,2H), 2.10 (s, 6H), 1.56 (p, J=7.5 Hz, 2H), 1.40 (s, 9H); LC-MS: 97.07%;380.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT1.85 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(1-(5-(aminomethyl) thiazol-2-yl)-1H-pyrazol-4-yl)-N,N-dimethylbutan-1-amine hydrochloride (448)

To a stirring solution of compound 447 (1 g, 2.63 mmol) in CH₂Cl₂ (10mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (3 mL) at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (2×5mL), hexane (5 mL) and dried in vacuo to afford crude compound 448 (750mg, HCl salt) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.1);LC-MS: 57.57%; 315.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 0.31 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of tert-butyl42-(4-(4-(diethylamino)butyl)-1H-pyrazol-1-yl)thiazol-5-yl)methyl)carbamate(447A)

To a stirring solution of compound 446 (2.0 g, 4.65 mmol) in THF (10 mL)in a sealed tube under inert atmosphere was added diethylamine (5 mL) atRT; heated to 80° C. and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was purified through silica gel column chromatographyusing 6% MeOH/CH₂Cl₂ to afford compound 447A (1.6 g, 85%) as pale brownsyrup. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); LC-MS: 99.53%; 408.2 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.00 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of4-(1-(5-(aminomethyl)thiazol-2-yl)-1H-pyrazol-4-yl)-N,N-diethylbutan-1-amine hydrochloride (448A)

To a stirring solution of compound 447A (1.6 g, 3.93 mmol) in CH₂Cl₂ (20mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (5 mL) at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (2×5mL), hexane (5 mL) and dried in vacuo to afford crude compound 448A (750mg, HCl salt) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.1);LC-MS: 57.57%; 315.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 0.31 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of ethyl (E)-3-(1-(5-(aminomethyl)thiazol-2-yl)-1H-pyrazol-4-yl) acrylate hydrochloride (451)

Synthesis of ethyl (E)-3-(1-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl)-1H-pyrazol-4-yl) acrylate (450)

To a stirring solution of methyl tert-butyl((2-(4-bromo-1H-pyrazol-1-yl) thiazol-5-yl) methyl) carbamate 442 (1.3g, 3.61 mmol) in DMF (50 mL) under inert atmosphere in a sealed tubewere added ethyl acrylate 449 (1.81 g, 18.10 mmol),diisopropylethylamine (2.0 mL, 10.86 mmol), purged under argonatmosphere for 30 min. To this were added P(o-tol)₃ (330 mg, 1.08 mmol),Pd(OAc)₂ (243 mg, 0.36 mmol) at RT; heated to 100° C. and stirred for 16h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was poured into ice-cold water (150 mL) andextracted with EtOAc (2×150 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to affordcrude. The crude was purified through silica gel column chromatographyusing 30% EtOAc/hexanes to afford compound 450 (550 mg, 40%) as anoff-white solid. TLC: 40% EtOAc/hexanes (R_(f): 0.4); ¹H NMR (400 MHz,DMSO-d₆): δ 8.90 (s, 1H), 8.32 (s, 1H), 7.65-7.55 (m, 2H), 7.47 (s, 1H),6.58 (d, J=16.1 Hz, 1H), 4.27 (d, J=5.9 Hz, 2H), 4.17 (q, J=7.1 Hz, 2H),1.40 (s, 9H), 1.25 (t, J=7.2 Hz, 3H); LC-MS: 89.66%; 379.0 (M⁺+1);(column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 1.97 min. 2.5 mM Aq.NH₄OOCH+5% ACN:ACN: 5%2.5 mM Aq. NH₄OOCH; 0.8 mL/min).

Synthesis of ethyl (E)-3-(1-(5-(aminomethyl)thiazol-2-yl)-1H-pyrazol-4-yl) acrylate hydrochloride (451)

To a stirring solution of compound 450 (150 mg, 0.39 mmol) in CH₂Cl₂ (5mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (1 mL) at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (2×5mL), dried in vacuo to afford compound 451 (110 mg, 89%; HCl salt) aswhite solid. TLC: 30% EtOAc/hexanes (R_(f): 0.1); ¹H NMR (500 MHz,DMSO-d₆): δ 8.93 (s, 1H), 8.45 (br s, 3H), 8.37 (s, 1H), 7.74 (s, 1H),7.61 (d, J=15.6 Hz, 1H), 6.59 (d, J=16.2 Hz, 1H), 4.31-4.30 (m, 2H),4.17 (q, J=7.0 Hz, 2H), 1.24 (t, J=7.0 Hz, 3H);

Synthesis of (2-(1H-pyrazol-1-yl) thiazol-5-yl) methanaminehydrochloride (455)

Synthesis of N-((2-chlorothiazol-5-yl) methyl)-1, 1,1-triphenylmethanamine (452)

To a stirring solution of (2-chlorothiazol-5-yl) methanaminehydrochloride 223 (1.0 g, 5.43 mmol) in CH₂Cl₂ (40 mL) under inertatmosphere were added triethyl amine (1.57 mL, 10.86 mmol), tritylchloride (1.57 mL, 6.46 mmol) at 0° C.; warmed to RT and stirred for 2h. The reaction was monitored by TLC; after completion of the reaction,the volatiles were removed in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 10%EtOAc/hexanes to afford compound 452 (1.5 g, 71%) as white solid. TLC:10% EtOAc/(R_(f): 0.8); ¹H-NMR (DMSO-d₆, 500 MHz): δ 7.46-7.40 (m, 5H),7.36-7.27 (m, 5H), 7.26-7.17 (m, 5H), 3.97 (br t, J=8.4 Hz, 1H),3.34-3.27 (m, 2H);

Synthesis of N-((2-(1H-pyrazol-1-yl) thiazol-5-yl) methyl)-1, 1,1-triphenylmethanamine (454)

To a stirring solution of compound 452 (2 g, 0.51 mmol) in DMF (15 mL)under inert atmosphere were added 1H-pyrazole 453 (70 mg, 1.02 mmol),cesium carbonate (333 mg, 1.02 mmol) at RT; heated to 100° C. andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with water (30 mL) andextracted with EtOAc (2×60 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel column flashchromatography using 5-7% EtOAc/hexanes to afford compound 454 (110 mg,51%) as an off-white solid. TLC: 15% EtOAc/hexanes (R_(f): 0.4). ¹H-NMR(DMSO-d₆, 400 MHz): δ 8.46 (d, J=2.6, 0.6 Hz, 1H), 7.86 (d, J=1.7 Hz,1H), 7.48-7.44 (m, 6H), 7.38-7.30 (m, 7H), 7.24-7.19 (m, 3H), 6.62 (dd,J=2.5, 1.8 Hz, 1H), 3.87 (t, J=8.4 Hz, 1H), 3.31 (s, 2H); LC-MS (Agilent6310 Ion trap): 99.52%; 423.2 (M+1)⁺; (column; Kinetex EVO C-18 (50×3.0mm, 2.6 um); RT 5.33 min. 2.5 mM Aq. NH₄OOCH:ACN; 0.8 mL/min).

Synthesis of (2-(1H-pyrazol-1-yl) thiazol-5-yl) methanaminehydrochloride (455)

To a stirring solution of compound 454 (200 mg, 0.47 mmol) in CH₂Cl₂ (5mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (2×10mL) and dried in vacuo to afford compound 455 (90 mg, 88%; HCl salt) asan off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H-NMR (DMSO-d₆,400 MHz): δ 8.56 (br s, 2H), 8.50 (d, J=2.6 Hz, 1H), 7.88 (d, J=1.5 Hz,1H), 7.72 (s, 1H), 6.66-6.64 (m, 1H), 4.28 (br s, 2H); LC-MS: 95.50%;181.9 (M+1)⁺; (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 0.69min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of (2-(2H-1, 2, 3-triazol-2-yl) thiazol-5-yl) methanaminehydrochloride (458A)

Synthesis of N-((2-(1H-1, 2, 3-triazol-1-yl) thiazol-5-yl)methyl)-1, 1,1-triphenylmethanamine (457A) & N-((2-(2H-1, 2, 3-triazol-2-yl)thiazol-5-yl) methyl)-1, 1, 1-triphenylmethanamine (457B)

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-1, 1,1-triphenylmethanamine 452 (1 g, 2.56 mmol) in DMF (15 mL) under inertatmosphere were added 1H-1, 2, 3-triazole 456 (354 mg, 5.12 mmol),cesium carbonate (2.5 g, 7.69 mmol) at RT; heated to 110° C. and stirredfor 32 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with water (100 mL) andextracted with EtOAc (2×80 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through neutral alumina flash columnchromatography using 5-10% EtOAc/hexanes to afford compound 457A (250mg) and 457B (230 mg) as white solids.

Analytical Data of 457A: TLC: 20% EtOAc/hexanes (R_(f): 0.3). ¹H NMR(400 MHz, DMSO-d₆): δ 8.87 (d, J=1.2 Hz, 1H), 8.05 (d, J=1.2 Hz, 1H),7.58 (s, 1H), 7.50-7.44 (m, 6H), 7.37-7.30 (m, 6H), 7.26-7.19 (m, 3H),4.07 (t, J=8.4 Hz, 1H), 3.40 (d, J=8.4 Hz, 2H);

Analytical Data of 457B: TLC: 20% EtOAc/hexanes (R_(f): 0.3). ¹H-NMR(DMSO-d₆, 400 MHz): δ 8.25 (s, 2H), 7.50 (s, 1H), 7.48-7.44 (m, 6H),7.34 (t, J=7.7 Hz, 6H), 7.25-7.20 (m, 3H), 4.02 (t, J=8.4 Hz, 1H), 3.38(d, J=8.2 Hz, 2H).

Synthesis of (2-(1H-1, 2, 3-triazol-1-yl) thiazol-5-yl) methanamine TFAsalt (458A)

To a stirring solution of compound 457A (200 mg, 0.47 mmol) in CH₂Cl₂(10 mL) under inert atmosphere were added trieythlsilane (0.15 mL, 0.94mmol), trifluoroacetic acid (0.2 mL, 2.36 mmol) at 0° C.; warmed to RTand stirred for 1 h. The reaction was monitored by TLC; after completionof the reaction, the volatiles were removed in vacuo to obtain thecrude, which was washed with n-hexane to afford compound 458A (85 mg,71) as white solid. TLC: 30% EtOAc/hexanes (R_(f): 0.2); ¹H-NMR(DMSO-d₆, 400 MHz): δ 8.92 (s, 1H), 8.46 (br s, 2H), 8.07 (s, 1H), 7.89(s, 1H), 4.39 (br s, 2H); LC-MS: 88.52%; 181.9 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 0.37 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(2H-1, 2, 3-triazol-2-yl) thiazol-5-yl) methanaminehydrochloride (458B)

To a stirring solution of N-((2-(2H-1, 2, 3-triazol-2-yl) thiazol-5-yl)methyl)-1, 1, 1-triphenylmethanamine 457B (230 mg, 0.54 mmol) in CH₂Cl₂(5 mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (3 mL)at 0° C.; warmed to RT and stirred for 3 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (2×10mL) and dried in vacuo to afford compound 458B (90 mg, 76%; HCl salt) aswhite solid. TLC: 30% EtOAc/hexanes (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400MHz): δ 8.56 (br s, 3H), 8.28 (s, 2H), 7.83 (s, 1H), 4.34 (s, 2H); LC-MS(Agilent 6310 Ion trap): 95.92%; 182.1 (M⁺+1); (column; X-Select CSHC-18, (150×4.6 mm, 3.5 μm); RT 5.53 min. 2.5 mM Aq. NH₄OAc:ACN; 1.0mL/min).

Synthesis of ethyl 1-(5-(aminomethyl)thiazol-2-yl)-1H-pyrazole-4-carboxylate TFA salt (461)

Synthesis of ethyl 1-(5-((tritylamino) methyl)thiazol-2-yl)-1H-pyrazole-4-carboxylate (460)

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-1, 1,1-triphenylmethanamine 452 (500 mg, 1.28 mmol) in DMF (10 mL) underinert atmosphere were added ethyl 1H-pyrazole-4-carboxylate 459 (180 mg,1.28 mmol), cesium carbonate (833 mg, 2.56 mmol) at RT; heated to 90° C.and stirred for 10 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(30 mL) and extracted with EtOAc (2×60 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelflash column chromatography using 20-25% EtOAc/hexanes to affordcompound 460 (200 mg, 32%) as white solid. TLC: 20% EtOAc/hexanes(R_(f): 0.3). ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.85 (s, 1H), 8.25 (s, 1H),7.45 (br d, J=7.4 Hz, 6H), 7.32 (t, J=7.7 Hz, 6H), 7.21 (t, J=7.3 Hz,3H), 4.27 (q, J=7.2 Hz, 2H), 3.96 (t, J=8.4 Hz, 1H), 3.34 (d, J=8.4 Hz,3H), 1.30 (t, J=7.1 Hz, 3H);

Synthesis of ethyl 1-(5-(aminomethyl)thiazol-2-yl)-1H-pyrazole-4-carboxylate TFA Salt (461)

To a stirring solution of compound 460 (200 mg, 0.40 mmol) in CH₂Cl₂ (20mL) under inert atmosphere were added trieythlsilane (0.12 mL, 0.80mmol), trifluoroacetic acid (0.16 mL, 2.02 mmol) at 0° C.; warmed to RTand stirred for 3 h. The reaction was monitored by TLC; after completionof the reaction, the volatiles were removed in vacuo to obtain thecrude, which was washed diethylether (2×10 mL) and dried in vacuo toafford compound 461 (100 mg, 71) as white solid. TLC: 30% EtOAc/hexanes(R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.91 (br s, 1H), 8.34 (br s,2H), 8.28 (s, 1H), 7.78 (s, 1H), 4.34 (d, J=4.0 Hz, 2H), 4.28 (q, J=7.2Hz, 2H), 1.30 (t, J=7.1 Hz, 3H).

Synthesis of 2-(4-(4-morpholinobutyl) phenyl) thiazol-5-yl) methanaminehydrochloride (468)

Synthesis of tert-butyl ((2-(4-bromophenyl) thiazol-5-yl) methyl)carbamate (463)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (10 g, 40.29) in DME:H₂O (4:1, 100 mL) were added(4-bromophenyl) boronic acid 462 (6.43 g, 32.16 mmol) and sodiumcarbonate (14.91 g, 140.73 mmol) in a sealed tube at RT and purged underargon for 30 min. Then Pd(dppf)Cl₂ (2.94 g, 4.02 mmol) was added at RT.The reaction mixture was heated to 100° C. and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (200 mL), and extracted withEtOAc (2×200 mL). The combined organic extracts were washed with brine(100 mL), dried over sodium sulfate, filtered and concentrated in vacuoto obtain the crude. The crude was purified through silica gel columnchromatography using 5% EtOAc/Hexane to afford compound 463 (2.5 g, 17%)as white solid. TLC: 20% EtOAc/hexanes (R_(f): 0.5). ¹H NMR (500 MHz,DMSO-d₆): δ 7.84 (d, J=8.1 Hz, 2H), 7.70 (d, J=9.3 Hz, 2H), 7.67 (s,1H), 7.57 (br s, 1H), 4.34 (br d, J=5.8 Hz, 2H), 1.39 (s, 9H)

Synthesis of tert-butyl ((2-(4-(4-hydroxybut-1-yn-1-yl) phenyl)thiazol-5-yl)methyl) carbamate (464)

To a stirring solution of compound 463 (2.5 g, 3.79 mmol) in triethylamine (30 mL) were added prop-2-yn-1-ol 443 (456 mg, 8.15 mmol), andcopper iodide (12 mg, 0.06 mmol) at RT in a sealed tube and purged underargon atmosphere for 15 min. To this were added Pd(PPh₃)₂Cl₂ (95 mg,1.13 mmol) at RT; heated to 60° C. and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the volatilesremoved under reduced pressure. The residue was diluted with water (20mL), and extracted with EtOAc (2×30 mL). The combined organic extractswere washed with brine (30 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 40-50% EtOAc/Hexane toafford crude compound 464 (2.8 g, crude) as pale yellow solid. TLC: 50%EtOAc/hexanes (R_(f): 0.3); LC-MS: 92.51%; 359.50 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.37 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-(4-hydroxybutyl) phenyl) thiazol-5-yl)methyl) carbamate (465)

To a stirring solution of tert-butyl ((2-(4-(4-hydroxybut-1-yn-1-yl)phenyl) thiazol-5-yl) methyl) carbamate 464 (1.3 g, 3.62 mmol) in MeOH(150 mL) under inert atmosphere was added 10% Pd/C (700 mg, 50% w/w) atRT and stirred under hydrogen atmosphere (balloon pressure) at RT for 16h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was filtered through celite and eluted with 20%MeOH/CH₂Cl₂ (200 mL). The filtrate was concentrated in vacuo to obtainthe crude. The crude was triturated with diethyl ether (15 mL) and driedin vacuo to afford compound 465 (800 mg, 61%) as colorless thick syrup.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (400 MHz, DMSO-d₆): δ 7.79 (d,J=8.2 Hz, 2H), 7.65 (s, 1H), 7.59-7.52 (m, 1H), 7.30 (d, J=8.2 Hz, 2H),4.40-4.27 (m, 3H), 3.41 (t, J=6.3 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H),1.68-1.53 (m, 2H), 1.51-1.41 (m, 2H), 1.40 (s, 9H);

Synthesis of 4-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenyl) butyl methanesulfonate (466)

To a stirring solution of compound 465 (250 mg, 0.69 mmol) in CH₂Cl₂ (15mL) under inert atmosphere were added triethyl amine (0.19 mL, 1.38mmol) and methanesulfonyl chloride (94 mg, 0.82 mmol) at 0° C.; warmedto RT and stirred for 3 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(50 mL), extracted with EtOAc (2×50 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toafford crude compound 466 (400 mg) as an off-white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.8); LC-MS: 93.89%; 441.0 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.63 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-(4-morpholinobutyl) phenyl) thiazol-5-yl)methyl) carbamate (467)

To a stirring solution of compound 466 (330 mg, crude) in THF (10 mL) ina sealed tube under inert atmosphere was added morpholine 302 (326 mg,3.75 mmol) at RT; heated to 70° C. and stirred for 8 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The residue was diluted with EtOAc (50 mL), washedwith water (50 mL). The organic extract was dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 3% MeOH/CH₂Cl₂to afford compound 467 (210 mg, 70%, over 2 steps) as colorless thicksyrup. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); LC-MS: 97.07%; 432.1 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.95 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(4-(4-morpholinobutyl) phenyl) thiazol-5-yl) methanaminehydrochloride (468)

To a stirring solution of compound 467 (210 mg, 0.48 mmol) in CH₂Cl₂ (10mL) was added 4 N HCl in 1, 4-dioxane (2 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with EtOAc (2×5 mL),diethyl ether (5 mL) and dried in vacuo to afford compound 468 (160 mg,90%; HCl salt) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2);¹H NMR (400 MHz, DMSO-d₆): δ 11.06 (br s, 1H), 8.57 (br s, 3H), 7.95 (s,1H), 7.85 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 4.33 (q, J=5.4 Hz,2H), 3.97-3.88 (m, 2H), 3.86-3.74 (m, 2H), 3.42-3.32 (m, 2H), 3.16-2.91(m, 4H), 2.71-2.62 (m, 2H), 1.80-1.57 (m, 4H);

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl)-N-(tert-butyl)butan-1-amine hydrochloride (471)

Synthesis of tert-butyl ((2-(4-(4-(tert-butylamino) butyl) phenyl)thiazol-5-yl) methyl) carbamate (470)

To a stirring solution of 4-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenyl) butyl methanesulfonate 466 (400 mg, 0.90 mmol) inDMF (10 mL) under inert atmosphere were added 2-methylpropan-2-amine 469(663 mg, 9.08 mmol) and potassium carbonate (250 mg, 1.81 mmol) in asealed tube at RT; heated to 70° C. and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with water (100 mL) and extracted with EtOAc (2×50mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 8% MeOH/CH₂Cl₂to afford crude compound 470 (260 mg) as colorless syrup. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.3). ¹H NMR (400 MHz, DMSO-d₆): δ 7.95 (s, 1H),7.79 (d, J=8.2 Hz, 2H), 7.65 (s, 1H), 7.54 (t, J=4.1 Hz, 1H), 7.31 (d,J=8.2 Hz, 2H), 4.32 (d, J=5.8 Hz, 2H), 3.22-3.10 (m, 2H), 2.62 (t, J=7.6Hz, 2H), 1.67-1.59 (m, 2H), 1.40 (s, 9H), 1.34-1.24 (m, 2H), 1.01 (s,9H); LC-MS: 98.88%; 191.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0mm, 2.7 μm); RT 2.04 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min).

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl)-N-(tert-butyl)butan-1-amine hydrochloride (471)

To a stirring solution of compound 470 (260 mg, 0.62 mmol) in CH₂Cl₂ (10mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (5 mL) at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (5mL) and dried in vacuo to afford compound 471 (190 mg, 86%; HCl salt) asan off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (500 MHz,DMSO-d₆): δ 8.89-8.54 (m, 3H), 7.96 (s, 1H), 7.85 (d, J=8.1 Hz, 2H),7.38 (d, J=8.1 Hz, 2H), 4.64 (br s, 2H), 4.37-4.31 (m, 2H), 2.89-2.79(m, 2H), 2.70-2.66 (m, 2H), 1.27 (s, 13H); LC-MS: 98.49%; 318.1 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.37 min. 0.025%Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(4-(4-(piperidin-1-yl) butyl) phenyl) thiazol-5-yl)methanamine hydrochloride (474)

Synthesis of tert-butyl 42-(4-(4-(piperidin-1-yl) butyl) phenyl)thiazol-5-yl) methyl) carbamate (473)

To a stirring solution of 4-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenyl) butyl methanesulfonate 466 (330 mg, 0.75 mmol) inTHF (5 mL) in a sealed tube under inert atmosphere was added piperidine472 (2 mL) at RT; heated to 90° C. and stirred for 6 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The crude was purified through silica gel columnchromatography using 5% MeOH/CH₂Cl₂ to afford compound 473 (220 mg, 69%)as brown syrup. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (DMSO-d₆, 400MHz): δ 7.79 (d, J=8.2 Hz, 2H), 7.65 (s, 1H), 7.54 (t, J=5.0 Hz, 1H),7.30 (d, J=8.2 Hz, 2H), 4.32 (d, J=6.0 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H),2.31-2.15 (m, 4H), 1.63-1.55 (m, 2H), 1.50-1.42 (m, 6H), 1.40 (s, 9H),1.37-1.32 (m, 4H); LC-MS: 97.07%; 432.1 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.95 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(4-(4-(piperidin-1-yl) butyl) phenyl) thiazol-5-yl)methanamine hydrochloride (474)

To a stirring solution of compound 473 (210 mg, 0.48 mmol) in CH₂Cl₂ (5mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (3 mL) at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (2×50mL), hexane (25 mL) and dried in vacuo to afford compound 474 (170 mg,HCl salt) as brown solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (400MHz, DMSO-d₆): δ 10.34 (br s, 1H), 8.63 (br s, 3H), 7.96 (s, 1H), 7.85(d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 4.33 (q, J=5.6 Hz, 2H),3.42-3.30 (m, 2H), 3.06-2.92 (m, 2H), 2.86-2.75 (m, 2H), 2.67 (t, J=7.5Hz, 2H), 1.85-1.59 (m, 10H);

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl)-N,N-diethylbutan-1-amine hydrochloride (476)

Synthesis of tert-butyl ((2-(4-(4-(diethylamino) butyl) phenyl)thiazol-5-yl) methyl) carbamate (475)

To a stirring solution of 4-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenyl) butyl methanesulfonate 466 (340 mg, 0.77 mmol) inTHF (10 mL) under inert atmosphere was added diethylamine 387 (3 mL) ina sealed tube at RT; heated to 90° C. and stirred for 6 h. The reactionwas monitored by TLC; after completion of the reaction, the volatileswere removed in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 5% MeOH/CH₂Cl₂+aqueousammonia (0.5 mL) to afford compound 475 (250 mg, 78%) as colorlesssyrup. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2). ¹H-NMR (DMSO-d₆, 400 MHz): δ7.77 (d, J=8.1 Hz, 2H), 7.63 (s, 1H), 7.52 (t, J=5.5 Hz, 1H), 7.28 (d,J=8.1 Hz, 2H), 4.30 (d, J=5.8 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 2.42-2.26(m, 8H), 1.56 (p, J=7.5 Hz, 2H), 1.37 (s, 9H), 0.90 (t, J=7.1 Hz, 6H);LC-MS: 99.61%; 418.2 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 2.04 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl)-N,N-diethylbutan-1-amine hydrochloride (476)

To a stirring solution of compound 475 (250 mg, 0.59 mmol) in CH₂Cl₂ (5mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (2 mL) at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with diethyl ether (5mL), n-hexane (5 mL) and dried in vacuo to afford compound 476 (150 mg,71%; HCl salt) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2);¹H-NMR (DMSO-d₆, 400 MHz): δ 10.51-10.23 (m, 1H), 8.63 (br s, 2H), 7.96(s, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 4.33 (q, J=5.5Hz, 2H), 3.12-2.99 (m, 6H), 2.71-2.65 (m, 2H), 1.75-1.61 (m, 4H), 1.20(t, J=7.2 Hz, 6H); LC-MS: 99.36%; 318.1 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.35 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-(4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl) butyl)acetamide hydrochloride (480)

Synthesis of tert-butyl ((2-(4-(4-azidobutyl) phenyl) thiazol-5-yl)methyl) carbamate (477)

To a stirring solution of 4-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenyl) butyl methanesulfonate 466 (510 mg, 1.15 mmol) inDMF (10 mL) under inert atmosphere was added sodium azide (113 mg, 1.70mmol) at RT and heated to 70° C. and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted water (50 mL) and extracted with EtOAc (2×75 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain crude compound 477 (550 mg) as paleyellow oil. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.8);

Synthesis of tert-butyl ((2-(4-(4-aminobutyl) phenyl) thiazol-5-yl)methyl) carbamate (478)

To a stirring solution of compound 477 (550 mg, crude) in THF:H₂O (4:1,30 mL) was added triphenyl phosphine (446 mg, 1.70 mmol) at 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The residue was diluted water (50 mL) and extracted with 10% MeOH/CH₂Cl₂(2×50 mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 10% MeOH/CH₂Cl₂ to affordcompound 478 (160 mg, 31%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.2); LC-MS: 97.99%; 362.1 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 1.95 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl ((2-(4-(4-acetamidobutyl) phenyl) thiazol-5-yl)methyl) carbamate (479)

To a stirring solution of compound 478 (160 mg, 0.44 mmol) in CH₂Cl₂ (10mL) under inert atmosphere were added triethyl amine (0.12 mL, 0.88mmol), acetyl chloride (52 mg, 0.66 mmol) at 0° C.; warmed to RT andstirred for 4 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was quenched with ice-cold water (50mL) and extracted with EtOAc (2×75 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 5% MeOH/CH₂Cl₂ to afford compound 479 (140 mg, 78%)as thick syrup. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.8); LC-MS: 98.01%; 404.1(M⁺+1); (column; Ascentis Express C-18, (50×3.0 mm, 2.7 μm); RT 2.29min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of N-(4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl) butyl)acetamide hydrochloride (480)

To a stirring solution of compound 479 (140 mg, 0.34 mmol) in CH₂Cl₂ (10mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (3 mL) at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with EtOAc (2×5 mL),diethyl ether (2×5 mL) and dried in vacuo to afford compound 480 (100mg, 89%; HCl salt) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f):0.2); ¹H NMR (DMSO-d₆, 400 MHz) δ=8.64 (br s, 3H), 7.95 (s, 1H), 7.83(d, J=7.9 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 4.32 (q, J=5.5 Hz, 2H),3.09-3.00 (m, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.78 (s, 3H), 1.59 (p, J=7.4Hz, 2H), 1.41 (p, J=7.2 Hz, 2H); LC-MS: 98.49%; 304.1 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.48 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl)phenyl)-N-isopropyl-N-methylbutan-1-amine hydrochloride (482)

Synthesis of tert-butyl ((2-(4-(4-(isopropyl(methyl) amino) butyl)phenyl) thiazol-5-yl) methyl) carbamate (481)

To a stirring solution of 4-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenyl) butyl methanesulfonate 466 (100 mg, 0.22 mmol) inDMF (5 mL) under inert atmosphere were added N-methylpropan-2-amine 412(50 mg, 0.68 mmol) and potassium carbonate (62 mg, 0.45 mmol) in asealed tube at RT and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith water (50 mL) and extracted with EtOAc (2×50 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 5% MeOH/CH₂Cl₂ to affordcompound 481 (80 mg) as colorless syrup. TLC: 5% MeOH/CH₂Cl₂ (R_(f):0.2). LC-MS: 80.36%; 418.1 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 2.00 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min).

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl)phenyl)-N-isopropyl-N-methylbutan-1-amine hydrochloride (482)

To a stirring solution of compound 481 (80 mg, 0.19 mmol) in CH₂Cl₂ (5mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with EtOAc (2×4 mL),diethyl ether (2×4 mL) and dried in vacuo to afford compound 482 (60 mg,HCl salt) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2);¹H-NMR (DMSO-d₆, 400 MHz): δ 10.02 (br s, 1H), 8.53 (br s, 3H), 7.95 (s,1H), 7.86 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.7 Hz, 2H), 4.34 (q, J=5.2 Hz,2H), 3.53-3.45 (m, 2H), 3.13-3.03 (m, 1H), 2.99-2.88 (m, 1H), 2.68 (brt, J=7.5 Hz, 2H), 2.60 (d, J=4.6 Hz, 3H), 1.79-1.54 (m, 4H), 1.31-1.17(m, 6H); LC-MS: 83.54%; 318.1 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 1.33 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min).

Synthesis of N-(4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl)butyl)-N-methylcyclopropanamine hydrochloride (484)

Synthesis of tert-butyl ((2-(4-(4-(cyclopropyl (methyl) amino) butyl)phenyl) thiazol-5-yl) methyl) carbamate (483)

To a stirring solution of 4-(4-(5-(((tert-butoxy carbonyl) amino)methyl) thiazol-2-yl) phenyl) butyl methanesulfonate 466 (200 mg, 0.45mmol) in DMF (5 mL) under inert atmosphere were addedN-methylcyclopropanamine hydrochloride 415 (98 mg, 0.90 mmol) andpotassium carbonate (125 mg, 0.90 mmol) in a sealed tube at RT andstirred for 48 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with water (100 mL) andextracted with EtOAc (2×75 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel column chromatographyusing 5% MeOH/CH₂Cl₂ to afford compound 483 (80 mg, 43%) as colorlessthick syrup. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2). LC-MS: 99.65%; 416.1(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.02 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-(4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl)butyl)-N-methylcyclopropanamine hydrochloride (484)

To a stirring solution of compound 483 (220 mg, 0.53 mmol) in CH₂Cl₂ (10mL) was added 4 N HCl in 1, 4-dioxane (3 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with EtOAc (2×10 mL),diethyl ether (2×10 mL) and dried in vacuo to afford compound 484 (125mg, 72%; HCl salt) as colorless thick syrup. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 10.14 (br s, 1H), 8.45 (br s,3H), 7.94 (s, 1H), 7.86 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 4.34(q, J=5.5 Hz, 2H), 3.24-3.14 (m, 2H), 2.78 (d, J=4.8 Hz, 3H), 2.72-2.65(m, 2H), 1.86-1.57 (m, 4H), 1.13-0.91 (m, 2H), 0.89-0.70 (m, 2H); LC-MS:94.90%; 316.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.34 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 1-(5-(aminomethyl) thiazol-2-yl) piperidin-4-onehydrochloride (488)

Synthesis of tert-butyl ((2-(4-hydroxypiperidin-1-yl) thiazol-5-yl)methyl) carbamate (486)

To a stirring solution tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (500 mg, 2.01 mmol) in N-methyl pyrrolidinone (10 mL)under inert atmosphere were added piperidin-4-ol 485 (408 mg, 4.03 mmol)and diisopropylethylamine (1.8 mL, 10.08 mmol) in a sealed tube andheated to 160° C. and stirred for 16 h. The reaction was monitored byTLC and LC-MS; after completion the reaction mixture was diluted withwater (50 mL) and extracted with EtOAc (2×50 mL). The combined organicextracts were dried over sodium sulphate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 4% MeOH/CH₂Cl₂ to afford compound 486 (350mg, 55%) as sticky solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H-NMR(DMSO-d₆, 500 MHz): δ 7.29 (t, J=5.5 Hz, 1H), 6.88 (s, 1H), 4.74 (d,J=4.0 Hz, 1H), 4.08 (d, J=5.8 Hz, 2H), 4.05-4.01 (m, 1H), 3.72-3.60 (m,3H), 3.15-3.07 (m, 2H), 1.85-1.71 (m, 2H), 1.45-1.40 (m, 2H), 1.38 (s,9H); LC-MS: 99.03%; 314.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0mm, 2.7 μm); RT 1.54 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min).

Synthesis of tert-butyl ((2-(4-oxopiperidin-1-yl) thiazol-5-yl) methyl)carbamate (487)

To a stirring solution of compound 486 (1.7 g, 5.43 mmol) in EtOAc (40mL) under inert atmosphere was added iodoxybenzoic acid (3.04 g, 10.86mmol) at 0° C.; heated to 70° C. and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas filtered through celite. The titrate was concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 3% MeOH/CH₂Cl₂ to afford compound 487 (650 mg,crude) as colorless syrup. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.6); LC-MS:48.21%; 312.2 (M⁺+1); (Column; X-select CSH C-18 (50×3 mm, 2.5 μm); RT3.37 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.0 mL/min).

Synthesis of 1-(5-(aminomethyl) thiazol-2-yl) piperidin-4-onehydrochloride (488)

To a stirring solution of compound 487 (750 mg, crude) in CH₂Cl₂ (10 mL)under inert atmosphere was added 4 N HCl in 1, 4-dioxane (1 mL) at 0°C.; warmed to RT and stirred for 3 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The crude was washed with EtOAc (5 mL) and dried in vacuo to affordcompound 488 (450 mg, 76%, HCl salt) as an off-white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f). 0.1); ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.36 (br s, 3H),7.30 (s, 1H), 4.10 (q, J=5.6 Hz, 2H), 3.83-3.78 (m, 4H), 2.52-2.49 (m,4H);

Synthesis of 1-(5-(aminomethyl) thiazol-2-yl)-1, 4-diazepan-5-onehydrochloride (492)

Synthesis of tert-butyl ((2-(4-(hydroxyimino) cyclohexyl) thiazol-5-yl)methyl) carbamate (488)

To a stirring solution of compound 487 (900 mg, 2.89 mmol) in EtOH (25mL) under argon atmosphere were added hydroxylamine hydrochloride (402mg, 5.78 mmol) and sodium acetate (474 mg, 5.78 mmol) at RT; heated toreflux and stirred for 12 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was filtered washedwith EtOAc and filtrate was concentrated in vacuo. The residue wasdiluted with water (20 mL) and extracted with EtOAc (2×20 mL). Thecombined organic extracts were washed with water and dried over sodiumsulfate, filtered and concentrated in vacuo to afford compound 488 (920mg crude) as brown syrupy. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR(DMSO-d₆, 500 MHz): δ 13.15 (br s, 1H), 8.29 (br s, 3H), 8.14 (s, 1H),8.05 (s, 1H), 7.76 (d, J=8.1 Hz, 2H), 7.69 (dd, J=8.4, 1.7 Hz, 1H),7.65-7.62 (m, 1H), 7.56 (d, J=8.4 Hz, 2H), 4.07 (q, J=5.8 Hz, 2H);LC-MS: 65.42%; 327.0 (M⁺+2); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 1.63 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of tert-butyl ((2-(5-oxo-1, 4-diazepan-1-yl) thiazol-5-yl)methyl) carbamate (491)

To a stirring solution of compound 488 (900 mg, 2.75 mmol) in acetone (5mL) was added sodium carbonate (875 mg, 8.25 mmol in 15 mL water) inwater (15 mL) and stirred for 5 min. To this was added p-toluenesulfonyl chloride 490 (786 mg, 4.12 mmol) at RT; and stirred for 16 h.The reaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The residue was diluted with water (20mL) and extracted with CH₂Cl₂ (2×20 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 8% MeOH/CH₂Cl₂ to afford compound 491 (460 mg, 51%)as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR(DMSO-d₆, 500 MHz): δ 13.15 (br s, 1H), 8.29 (br s, 3H), 8.14 (s, 1H),8.05 (s, 1H), 7.76 (d, J=8.1 Hz, 2H), 7.69 (dd, J=8.4, 1.7 Hz, 1H),7.65-7.62 (m, 1H), 7.56 (d, J=8.4 Hz, 2H), 4.07 (q, J=5.8 Hz, 2H);LC-MS: 87.76%; 327.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 1.56 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 1-(5-(aminomethyl) thiazol-2-yl)-1, 4-diazepan-5-onehydrochloride (492)

To a stirring solution of compound 491 (450 mg, 1.38 mmol) in CH₂Cl₂ (10mL) under argon atmosphere was added 4 N HCl in 1, 4-dioxane (15 mL) at0° C.; warmed to RT and stirred for 6 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude washed with diethyl ether (40 mL), hexane (30 mL) anddried in vacuo to afford compound 492 (300 mg crude) as an off-whitesolid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 500 MHz): δ13.15 (br s, 1H), 8.29 (br s, 3H), 8.14 (s, 1H), 8.05 (s, 1H), 7.76 (d,J=8.1 Hz, 2H), 7.69 (dd, J=8.4, 1.7 Hz, 1H), 7.65-7.62 (m, 1H), 7.56 (d,J=8.4 Hz, 2H), 4.07 (q, J=5.8 Hz, 2H); LC-MS: 85.76%; 227 (M⁺+1);(column; Kinetex EVO C-18, (50×3.0 mm, 2.6 μm); RT 0.36 min. 2.5 mM Aq.NH4OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of (2-(morpholinomethyl) thiazol-5-yl) methanamine (500)

Synthesis of 5-(((tert-butyldimethylsilyl) oxy) methyl) thiazole (494)

To a stirring solution of thiazol-5-ylmethanol 493 (10 g, 86.95 mmol) inCH₂Cl₂ (100 mL) under inert atmosphere were added imidazole (11.82 g,173.9 mmol) and tert-Butyldimethylsilyl chloride (15.72 g, 104.31 mmol)at 0° C.; warmed to RT and stirred for 2 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasdiluted with water (200 mL) and extracted with CH₂Cl₂ (2×200 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to afford compound 494 (19 g, 95%) as pale yellowliquid. TLC: 20% EtOAc/hexanes (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400 MHz):δ 9.02 (s, 1H), 7.79 (s, 1H), 4.92 (s, 2H), 0.87 (s, 9H), 0.07 (s, 6H);LC-MS: 99.03%; 229.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 2.91 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 5-(((tert-butyldimethylsilyl) oxy) methyl)thiazole-2-carbaldehyde (495)

To a stirring solution of 5-(((tert-butyldimethylsilyl) oxy) methyl)thiazole compound 494 (2 g, 8.71 mmol) in dry THF (20 mL) under inertatmosphere was added n-butyl lithium (1.6 M solution in hexane, 8.16 mL,13.07 mmol) dropwise for 10 min at −78° C. and stirred for 1 h. To thiswas added DMF (1.35 mL, 17.43 mmol) at −78° C. and stirred at the sametemperature for 2 h. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was quenched with saturatedammonium chloride solution (10 mL) and extracted with EtOAc (2×100 mL).The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to afford compound 495 (2 g, 89%) as colorlessliquid. TLC: 30% EtOAc/hexanes (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400 MHz):δ 9.89 (s, 1H), 8.10 (s, 1H), 5.02 (s, 2H), 0.89 (s, 9H), 0.10 (s, 6H);LC-MS (Agilent 6310 Ion trap): 98.45%; 258.2 (M⁺+1); (column; X SelectC-18 (50×3.0 mm, 2.5 um); RT 5.02 min. 2.5 mM Aq. NH₄OOCH:ACN, 0.8mL/min).

Synthesis of 4-((5-(((tert-butyldimethylsilyl) oxy) methyl)thiazol-2-yl) methyl) morpholine (496)

To a stirring solution of compound 495 (2 g, 7.78 mmol) in 1,2-dichloroethane (20 mL) under inert atmosphere were added morpholine(812 mg, 9.33 mmol) and sodium triacetoxyborohydride (3.3 g, 15.56 mmol)at 0° C.; warmed to RT and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasquenched with ice-cold water (100 mL) and extracted with CH₂Cl₂ (2×100mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 10-50%EtOAc/hexanes to afford compound 496 (1.3 g, 51%) as colorless thicksyrup. TLC: 30% EtOAc/hexanes (R_(f): 0.1); ¹H NMR (DMSO-d₆, 500 MHz): δ7.54 (s, 1H), 4.85 (s, 2H), 3.76 (s, 2H), 3.62-3.53 (m, 4H), 2.49-2.45(m, 4H), 0.86 (s, 9H), 0.07 (s, 6H); LC-MS: 94.28%; 329.0 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.06 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(morpholinomethyl) thiazol-5-yl) methanol (497)

To a stirring solution of compound 496 (1.3 g, 3.96 mmol) in THF (30 mL)under inert atmosphere was added tetrabutylammonium fluoride (1.0 Msolution in THF, 3.96 mL, 5.94 mmol) at 0° C.; warmed to RT and stirredfor 2 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was quenched with water (100 mL) andextracted with EtOAc (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel flash columnchromatography using 10-50% EtOAc/hexanes to afford compound 497 (700mg, 82%) as thick syrup. TLC: 50% EtOAc/hexanes (R_(f): 0.1); ¹H-NMR(DMSO-d₆, 400 MHz): δ 7.51 (s, 1H), 5.48 (t, J=5.7 Hz, 1H), 4.63 (dd,J=5.6, 0.8 Hz, 2H), 3.76 (s, 2H), 3.61-3.57 (m, 4H), 2.49-2.45 (m, 4H);LC-MS: 98.60%; 215.0 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm, 2.6um); RT 0.94 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH,0.8 mL/min);

Synthesis of 4-((5-(chloromethyl) thiazol-2-yl) methyl) morpholine (498)

To a stirring solution of compound 497 (700 mg, 3.25 mmol) in CH₂Cl₂ (20mL) under inert atmosphere were added triethyl amine (1.38 mL, 9.74mmol) at 0° C. and stirred for 10 min. To this was added methanesulfonylchloride (0.3 mL, 3.90 mmol) at 0° C.; warmed to RT and stirred for 2 h.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was quenched with saturated NaHCO₃ solution (50 mL) andextracted with EtOAc (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to affordcrude compound 498 (700 mg, 93%) as pale brown liquid. TLC: 30%EtOAc/hexanes (R_(f): 0.4); LC-MS: 89.79%; 232.9 (M⁺+1); (column;Ascentis Express C-18, (50×3.0 mm, 2.7 μm); RT 0.58 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-((5-(azidomethyl) thiazol-2-yl) methyl) morpholine (499)

To a stirring solution of compound 498 (700 mg, 3.01 mmol) in DMF (20mL) under inert atmosphere was added sodium azide (580 mg, 9.05 mmol) at0° C.; warmed to RT and stirred for 16 h. The reaction was monitored byTLC and LC-MS; after completion of the reaction, the reaction mixturewas diluted with ice-cold water (100 mL) and extracted with EtOAc (2×100mL). The combined organic extracts were dried over sodium sulphate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel flash column chromatography using 10-30%EtOAc/hexanes to afford compound 499 (400 mg, 70%) as colorless thicksyrup. TLC: 30% EtOAc/hexanes (R_(f): 0.5); ¹H-NMR (DMSO-d₆, 400 MHz): δ7.70 (s, 1H), 4.70 (s, 2H), 3.80 (s, 2H), 3.62-3.58 (m, 4H), 2.51-2.49(m, 4H);

Synthesis of (2-(morpholinomethyl) thiazol-5-yl) methanamine (500)

To a stirring solution of compound 499 (400 mg, 1.67 mmol) in THF:H₂O(4:1, 10 mL) was added triphenyl phosphine (877 mg, 3.34 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC and LC-MS; aftercompletion of the reaction, the reaction mixture was quenched with water(100 mL) and extracted with EtOAc (2×100 mL). The combined organicextracts were dried over sodium sulphate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelflash column chromatography using 4-5% MeOH/CH₂Cl₂ to afford compound500 (200 mg, 56%) as colorless thick syrup. TLC: 10% MeOH/CH₂Cl₂ (R_(f):0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 7.48 (s, 1H), 3.90 (s, 2H), 3.74 (s,2H), 3.63-3.56 (m, 4H), 2.97-2.72 (m, 2H), 2.48-2.45 (m, 4H); LC-MS:99.68%; 213.9 (M⁺+1); (Column; X-select CSH C-18 (150×4.6 mm, 3.5 μm);RT 1.31 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.0 mL/min).

Synthesis of azepan-3-ol hydrochloride (503)

Synthesis of tert-butyl 3-hydroxyazepane-1-carboxylate (502)

To a stirring solution of tert-butyl 3-oxoazepane-1-carboxylate 501 (500mg, 2.34 mmol) in MeOH (10 mL) under argon atmosphere was added sodiumborohydride (134 mg, 3.52 mmol) at 0° C.; warmed to RT and stirred for 4h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was quenched with ice-cold water (20 mL) andextracted with CH₂Cl₂ (2×50 mL). The combined organic extracts weredried over sodium sulfate and concentrated in vacuo to afford compound502 (450 mg, 89%) as colorless thick syrup. TLC: 30% EtOAc/hexanes(R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 4.67 (t, J=4.4 Hz, 1H),3.81-3.43 (m, 3H), 3.08-2.88 (m, 1H), 2.80-2.65 (m, 1H), 1.72-1.58 (m,4H), 1.56-1.33 (m, 9H), 1.30-1.17 (m, 1H).

Synthesis of azepan-3-ol hydrochloride (503)

To a stirring solution of compound 502 (450 mg, 2.09 mmol) in CH₂Cl₂ (10mL) was added 4 N HCl in 1, 4-dioxane (2 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was washed with CH₂Cl₂ (5 mL), n-pentane (10 mL) anddried in vacuo to afford compound 503 (200 mg, 63%) as an off-whitesolid. TLC: 30% EtOAc/hexanes (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ9.27 (br s, 1H), 8.52 (br s, 1H), 5.35-5.25 (m, 1H), 4.03-3.96 (m, 1H),3.15-2.94 (m, 4H), 1.85-1.44 (m, 6H).

Synthesis of (2-(oxazol-5-yl) thiazol-5-yl) methanamine (508)

Synthesis of (2-(oxazol-5-yl)thiazol-5-yl)methanol (505)

To a stirring solution of 5-(((tert-butyldimethylsilyl) oxy) methyl)thiazole-2-carbaldehyde 495 (600 mg, 2.33 mmol) in dry THF (20 mL) underinert atmosphere were added 1-((isocyanomethyl)sulfonyl)-4-methylbenzene 504 (455 mg, 2.33 mmol) and potassiumcarbonate (322 mg, 2.33 mmol) at RT; heated to 80° C. and stirred for 3h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture poured into ice-cold water (10 mL) and extractedwith CH₂Cl₂ (2×100 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using 3%MeOH/CH₂Cl₂ to afford compound 505 (200 mg, 53%) as white semi solid.TLC: 50% EtOAc/hexanes (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.56(s, 1H), 7.80-7.78 (m, 2H), 5.70 (t, J=5.7 Hz, 1H), 4.73 (dd, J=5.6, 0.9Hz, 2H); LC-MS: 94.97%; 182.9 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0mm, 2.6 um); RT 1.066 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5% 2.5 mMAq.NH₄OOCH, 0.8 mL/min).

Synthesis of 5-(5-(chloromethyl) thiazol-2-yl) oxazole (506)

To a stirring solution of compound 505 (200 mg, 1.09 mmol) in CH₂Cl₂ (5mL) under inert atmosphere were added triethyl amine (0.317 mL, 2.19mmol), methanesulfonyl chloride (0.168 mL, 2.19 mmol) at 0° C.; warmedto RT and stirred for 1 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was poured intoice-cold water (50 mL) and extracted with CH₂Cl₂ (2×25 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to afford crude compound 506 (200 mg) as colorlesssyrup. Which was taken forward for next step without furtherpurification. TLC: 20% EtOAc/hexanes (R_(f): 0.8);

Synthesis of 5-(5-(azidomethyl) thiazol-2-yl) oxazole (507)

To a stirring solution of compound 506 (200 mg, crude) in DMF (5 mL)under inert atmosphere was added sodium azide (130 mg, 2.00 mmol) at 0°C.; warmed to RT and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was pouredinto ice-cold water (50 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 20% EtOAc/hexanes toafford compound 507 (100 mg, 48%) as thick brown syrup. TLC: 20%EtOAc/hexanes (R_(f). 0.6); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.60 (s, 1H),7.98 (s, 1H), 7.86 (s, 1H), 4.83 (s, 2H); LC-MS: 95.22%; 207.9 (M⁺+1);(column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 2.00 min. 2.5 mM Aq.NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of (2-(oxazol-5-yl) thiazol-5-yl) methanamine hydrochloride(508)

To a stirring solution of compound 507 (100 mg, 0.48 mmol) in THF:H₂O(4:1, 5 mL) was added triphenyl phosphine (253 mg, 0.96 mmol) at RT andstirred for 6 h. The reaction was monitored by TLC and LC-MS; aftercompletion of the reaction; the volatiles were removed in vacuo toobtain the crude amine (200 mg crude).

To the above crude amine (200 mg) in CH₂Cl₂ (5 mL) was added 4 N HCl in1, 4-dioxane (1 mL) under inert atmosphere at 0° C.; warmed to RT andstirred for 1 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The crude washed withEtOAc (5 mL) and dried in vacuo to afford compound 508 (85 mg, HCl salt,crude) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.1);

Synthesis of (2-(oxazol-2-yl) thiazol-5-yl) methanamine hydrochloride(512)

Synthesis of 2-(tributylstannyl) oxazole (510)

To a stirring solution of oxazole 509 (2 g, 28.98 mmol) in dry THF (50mL) under inert atmosphere was added n-butyl lithium (19.9 mL, 31.88mmol, 1.6 M solution in hexane) at −78° C. and stirred for 1 h. To thiswas added a tributyltin chloride (7.85 mL, 28.98 mmol) at −78° C.;warmed to RT and stirred for 2 h.

The reaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The residue was diluted with hexane(100 mL), the obtained solid was filtered through celite and thefiltrate was concentrated in vacuo to afford crude compound 510 (8 g) ascolorless liquid which was taken for next step without furtherpurification. TLC: 10% EtOAc/hexanes (R_(f): 0.8);

Synthesis of tert-butyl ((2-(oxazol-2-yl) thiazol-5-yl) methyl)carbamate (511)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (750 mg, 3.01 mmol) in 1, 4-dioxane (20 mL) was added2-(tributylstannyl) oxazole 510 (4.32 g, 12.07 mmol) and purged underargon atmosphere for 30 min. To this was added Pd(PPh₃)₄ (348 mg, 0.30mmol) at RT; heated to 100° C. and stirred for 16 h. The reaction wasmonitored by TLC; after completion the reaction the volatiles wereremoved in vacuo to obtain the crude. The crude was purified throughsilica gel column chromatography using 30% EtOAc/hexanes and furtherpurified by preparative HPLC purification to afford compound 511 (100mg, 12%) as thick syrup. TLC: 30% EtOAc/hexanes (R_(f): 0.2); ¹H-NMR(DMSO-d₆, 500 MHz): δ 8.32 (s, 1H), 7.83 (s, 1H), 7.63 (t, J=6.1 Hz,1H), 7.46 (s, 1H), 4.37 (br d, J=5.8 Hz, 2H), 1.40 (s, 9H); LC-MS:99.93%; 281.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 2.06 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of (2-(oxazol-2-yl) thiazol-5-yl) methanamine hydrochloride(512)

To a stirring solution of compound 511 (100 mg, 0.35 mmol) in CH₂Cl₂ (5mL) was added 4 N HCl in 1, 4-dioxane (0.5 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 1 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude which was washed with EtOAc (10 mL) and driedin vacuo to afford compound 512 (70 mg, 90%; HCl salt) as an off-whitesolid. TLC: 5% MeOH/to CH₂Cl₂ (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ8.55 (br s, 3H), 8.37 (s, 1H), 8.10 (s, ¹H), 7.51 (d, 1H), 4.40 (q,J=5.6 Hz, 2H); LC-MS: 97.38%; 181.9 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 0.29 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min).

Synthesis of methyl (3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)propyl)-L-prolinate hydrochloride (517)

Synthesis of methyl L-prolinate hydrochloride (515)

To a stirring solution of L-proline 514 (5 g, 43.47 mmol) in MeOH (75mL) under inert atmosphere was added thionyl chloride (3.15 mL, 65.21mmol) drop wise at 0° C. for 15 min; and heated to reflux for 3 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo to obtain the crude compound 515 (6 gsalt, quantitative) as colourless liquid. This material was taken tonext step without further purification. TLC: 10% MeOH/CH₂Cl₂ (R_(f).0.4); ¹H NMR (400 MHz, DMSO-d₆): δ 10.85-10.21 (m, 1H), 9.33-8.59 (m,1H), 4.40-4.18 (m, 1H), 4.05-3.82 (m, 1H), 3.75 (s, 3H), 3.29-3.16 (m,2H), 2.32-2.18 (m, 1H), 2.06-1.82 (m, 2H);

Synthesis of 3-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenoxy) propyl trifluoromethanesulfonate (513)

To a stirring solution of compound 385 (100 mg, 0.27 mmol) in CH₂Cl₂ (10mL) under argon atmosphere were added triethylamine (0.11 mL, 0.82 mmol)and triflic anhydride (0.1 mL, 0.54 mmol), at −40° C. and stirred for 2h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was diluted with water (20 mL) and extracted withCH₂Cl₂ (2×20 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude compound513 (120 mg) as viscous syrup. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.6);

Synthesis of methyl (3-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenoxy) propyl)-L-prolinate (516)

To a stirring solution of compound 513 (2.7 g, 5.44 mmol) in CH₂Cl₂ (20mL) under argon atmosphere were added triethylamine (1.5 mL, 10.88 mmol)and compound 515 (1.4 g, 10.88 mmol), at −40° C. and stirred for 5 min.warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (50 mL) and extracted with CH₂Cl₂ (2×60 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelflash column chromatography using 2% MeOH/CH₂Cl₂ to afford compound 516(1.1 g, 42% for 2 steps) as viscous syrup. TLC: 5% MeOH/CH₂Cl₂ (R_(f):0.4); ¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (d, J=8.9 Hz, 2H), 7.60 (s, 1H),7.52 (t, J=5.6 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 4.30 (d, J=5.9 Hz, 2H),4.06 (t, J=6.3 Hz, 2H), 3.56 (s, 3H), 3.23-3.14 (m, 1H), 3.03-3.00 (m,1H), 2.82-2.73 (m, 1H), 2.56-2.53 (m, 1H), 2.40-2.33 (m, 1H), 2.07-1.89(m, 1H), 1.90-1.73 (m, 5H), 1.40 (s, 9H); LC-MS: 96.16%; 476.2 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.97 min. 0.025%Aq. TFA+5% ACN: ACN+; 5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of methyl (3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)propyl)-L-prolinate hydrochloride (517)

To a stirring solution of compound 516 (100 mg, 0.21 mmol) in CH₂Cl₂ (5mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under argon atmosphere at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was triturated with diethyl ether (5 mL) and EtOAc (5mL) and dried in vacuo to afford compound 517 (60 mg salt; 69%) as thicksyrup. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (500 MHz, DMSO-d₆): δ8.54 (br s, 3H), 7.92-7.85 (m, 3H), 7.08 (d, J=8.7 Hz, 2H), 4.51 (q,J=7.9 Hz, 1H), 4.32 (q, J=5.2 Hz, 2H), 4.15 (t, J=5.8 Hz, 2H), 3.79 (s,3H), 3.75-3.64 (m, 2H), 3.56-3.47 (m, 1H), 3.35-3.18 (m, 2H), 2.47-2.37(m, 1H), 2.21-2.04 (m, 4H); LC-MS: 94.78%; 376.1 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.23 min. 0.025% Aq.TFA+5% ACN: ACN+; 5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of 2, 2, 2-trifluoro-1-(((2-(4-isopropyl-1H-pyrazol-1-yl)thiazol-5-yl) methyl)-14-azanyl) ethan-1-one (519)

Synthesis of 2-(1-(5-((tritylamino) methyl)thiazol-2-yl)-1H-pyrazol-4-yl) propan-2-ol (518)

To a stirring solution of ethyl 1-(5-((tritylamino) methyl)thiazol-2-yl)-1H-pyrazole-4-carboxylate 452 (2.5 g, 5.06 mmol) inanhydrous THF (20 mL) under inert atmosphere was added methylmagnesiumbromide (13 mL, 25.30 mmol, 2 M sol. In diethylether) at −10° C.; warmedto RT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withsaturated ammonium chloride solution (60 mL) and extracted with EtOAc(2×100 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel flash column chromatography using20-25% EtOAc/hexanes to afford compound 518 (1 g, 42%) as an off-whitesolid. TLC: 20% EtOAc/hexanes (R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ8.23 (s, 1H), 7.79 (s, 1H), 7.47-7.45 (m, 5H), 7.38-7.30 (m, 8H),7.26-7.19 (m, 4H), 3.34-3.31 (m, 2H), 5.07 (s, 1H), 1.46 (s, 6H);

Synthesis of (2-(4-isopropyl-1H-pyrazol-1-yl) thiazol-5-yl)methanamineTFA salt (519)

To a stirring solution of compound 518 (300 mg, 0.62 mmol) in CH₂Cl₂ (10mL) under inert atmosphere were added trifluoroacetic acid (0.24 mL,3.12 mmol), trieythlsilane (0.2 mL, 1.25 mmol) at 0° C.; warmed to RTand stirred for 1 h. The reaction was monitored by TLC; after completionof the reaction, the volatiles were removed in vacuo to obtain thecrude, which was washed diethylether (2×10 mL) and dried in vacuo toafford crude compound 519 (150 mg, 68%) as white solid. TLC: 30%EtOAc/hexanes (R_(f): 0.2); 41 NMR (DMSO-d₆, 400 MHz): δ 8.37 (br s,3H), 8.26 (s, 1H), 7.80 (s, 1H), 7.66 (s, 1H), 4.30 (s, 2H), 2.91-2.84(m, 1H), 1.22 (d, J=6.9 Hz, 6H); LC-MS: 82.87%; 223.1 (M+1)⁺; (column;Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 2.62 min. 2.5 mM Aq.NH₄OOCH:ACN; 0.8 mL/min).

Synthesis of Synthesis of 1-(((2-(4-((3-(dimethylamino) azetidin-1-yl)methyl) phenyl) thiazol-5-yl) methyl)-14-azanyl)-2, 2,2-trifluoroethan-1-one (524A)

Synthesis of tert-butyl ((2-(4-formylphenyl) thiazol-5-yl) methyl)carbamate (520)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (1 g, 4.02 mmol) in DME:H₂O (4:1, 15 mL) were added(4-formylphenyl) boronic acid (905 mg, 6.03 mmol) and sodium carbonate(1.49 g, 14.08 mmol) in a sealed tube at RT and purged under argon for30 min. Then Pd(dppf)Cl₂ (294 mg, 0.40 mmol) was added at RT. Thereaction mixture was heated to 90-95° C. and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (30 mL), and extracted withEtOAc (2×30 mL). The combined organic extracts were washed with brine(30 mL), water (10 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 15% EtOAc/Hexane toafford compound 520 (600 mg, 47%) as pale yellow solid. TLC: 40%EtOAc/hexanes (R_(f): 0.4). ¹H NMR (500 MHz, DMSO-d₆): δ 10.05 (s, 1H),8.12 (d, J=8.1 Hz, 2H), 8.01 (d, J=8.1 Hz, 2H), 7.80 (s, 1H), 7.60 (brs, 1H), 4.37 (d, J=5.8 Hz, 2H), 1.40 (s, 9H); LC-MS: 93.26%; 318.9(M⁺+1) (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 2.91 min. 2.5mM NH₄OOCH in water+5% ACN: ACN+5% 2.5 mM NH₄OOCH in water, 0.8 mL/min).

Synthesis of tert-butyl 3-(dimethylamino) azetidine-1-carboxylate (522)

To a stirring solution of compound 521 (2.5 g, 14.53 mmol) in 1,2-dichloro ethane (25 mL) were added formaldehyde solution (36% in H₂O)(4.25 mL) and sodium triacetoxy borohydride (27.7 g, 13.08 mmol) at RTunder inert atmosphere. The reaction mixture was stirred at RT for 2 h.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (30 mL), basified with saturatedsodium bicarbonate solution (20 mL) to pH˜8 and extracted with EtOAc(2×30 mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude compound 522 (2.2g, 75%) as pale yellow liquid. LC-MS: 88.00%; 101.3 (M⁺+1) (des-boc)(column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 0.36 min. 5 mM AqNH₄OAc+ACN: 0.8 mL/min).

Synthesis of 1-(3-(dimethylamino)-1I4-azetidin-1-yl)-2, 2,2-trifluoroethan-1-one (523)

To a stirring solution of compound 522 (2.2 g, 11 mmol) in CH₂Cl₂ (20mL) was added trifluoroacetic acid (6 mL) at 0° C. under inertatmosphere. The reaction mixture was gradually warmed to RT and stirredfor 8 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo. The crude washed withtriturated with ether (20 mL) and dried in vacuo to obtain crudecompound 523 (1.8 g, 76%) as white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f):0.1); LC-MS: 80.67%; 101.3 (M⁺+1) (column; Atlantis T3, (150×4.6 mm, 3μm); RT 2.41 min. 2.5 mM Aq NH₄OAc:ACN, 1.0 mL/min).

Synthesis of tert-butyl ((2-(4-((3-(dimethylamino) azetidin-1-yl)methyl) phenyl) thiazol-5-yl) methyl) carbamate (524)

To a stirring solution of compound 520 (500 mg, 1.57 mmol) and compound523 (235 mg, 2.35 mmol) in CH₂Cl₂ (15 mL) were added potassium carbonate(260 mg, 1.88 mmol), sodium triacetoxy borohydride (666 mg, 3.14 mmol)and molecular sieves (500 mg) at RT under inert atmosphere. The reactionmixture was stirred at RT for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (15 mL), basified with saturated sodium bicarbonate solution (15mL) to pH˜8 and extracted with EtOAc (2×15 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 6-10% MeOH/CH₂Cl₂ to afford compound 524(400 mg, 63%) as pale yellow syrup. ¹H NMR (500 MHz, DMSO-d₆): δ 7.83(d, J=7.5 Hz, 2H), 7.67 (s, 1H), 7.58-7.53 (m, 1H), 7.38 (d, J=8.1 Hz,2H), 4.33 (d, J=5.2 Hz, 2H), 3.63 (s, 2H), 3.66-3.59 (m, 2H), 2.93-2.81(m, 3H), 2.03 (s, 6H), 1.40 (s, 9H); LC-MS: 98.20%; 403.2 (M⁺+1)(column; Ascentis Express C-18, (50×3.0 mm, 2.7 μm); RT 1.69 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 1-(((2-(4-((3-(dimethylamino) azetidin-1-yl) methyl)phenyl) thiazol-5-yl) methyl)-14-azanyl)-2, 2, 2-trifluoroethan-1-one(524A)

To a stirring solution of compound 524 (500 mg, 1.24 mmol) in CH₂Cl₂ (5mL) was added trifluoroacetic acid (2 mL) at 0° C. under inertatmosphere. The reaction mixture was gradually warmed to RT and stirredfor 8 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo. The crude washed withtriturated with ether (10 mL) and dried in vacuo to obtain crudecompound 524A (390 mg, 75%) as pale yellow solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.1); LC-MS: 94.59%; 303.2 (M⁺+1); (column; Atlantis T3,(150×4.6 mm, 3 μm); RT 6.45 min. 2.5 mM Aq NH₄OAc:ACN, 1.0 mL/min).

Synthesis of (2-(1-methyl-1H-pyrazol-3-yl) thiazol-5-yl) methanamine TFASalt (528)

Synthesis of 1-methyl-3-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazole (526)

To a stirring solution of 3-bromo-1-methyl-1H-pyrazole 525 (1 g, 6.25mmol) in 1, 4-dioxane (60 mL) under inert atmosphere were addedbispinacolato diboron (1.73 g, 6.83 mmol), potassium acetate (1.82 g,18.63 mmol) at RT and purged under argon atmosphere for 20 min, addedPd(dppf)Cl₂ (454 mg, 0.62 mmol) and heated to 120° C. and stirred for 3h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was filtered through celite. The filtrate wasconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 20% EtOAc/hexanes toafford compound 526 (2.4 g, crude) as brown thick syrup. The crude wascarried forward for next step without further purification. TLC: 50%EtOAc/hexanes (R_(f): 0.3);

Synthesis of tert-butyl 42-(1-methyl-1H-pyrazol-3-yl) thiazol-5-yl)methyl) carbamate (527)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (500 mg, 2.01 mmol) in 1, 2 dimethoxy ethane:H₂O (4:1, 75mL) under inert atmosphere were added 1-methyl-3-(4, 4, 5,5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole 526 (3.9 g, crude),sodium carbonate (750 mg, 7.08 mmol) and purged under argon atmospherefor 20 min. To this was added Pd(PPh₃)₄ (270 mg, 0.23 mmol) at RT;heated to 110° C. and stirred for 16 h. The reaction was monitored byTLC; after completion the volatiles were removed in vacuo to obtain thecrude. The residue was diluted with water (50 mL) and extracted withEtOAc (3×50 mL). The combined organic extracts were dried over sodiumsulfate and concentrated in vacuo to obtain the crude. The crude waspurified by preparative HPLC purification to afford compound 527 (160mg, 27%) as an off-white solid. TLC: 70% EtOAc/hexanes (R_(f): 0.4);¹H-NMR (DMSO-d₆, 400 MHz): δ 7.80 (d, J=2.3 Hz, 1H), 7.59 (s, 1H), 7.52(br t, J=5.3 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H), 4.30 (br d, J=5.8 Hz, 2H),3.31 (s, 3H), 1.40 (s, 9H); LC-MS: 96.60%; 294.9 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.04 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-(1-methyl-1H-pyrazol-3-yl) thiazol-5-yl) methanamine TFAsalt (528)

To a stirring solution of tert-butyl ((2-(1-methyl-1H-pyrazol-3-yl)thiazol-5-yl) methyl) carbamate 527 (50 mg, 0.17 mmol) in CH₂Cl₂ (3 mL)under inert atmosphere was added trifluoroacetic acid (0.06 mL) at 0°C.; warmed to RT and stirred for 8 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo toobtain the crude. The crude was titurated with diethylether (2×5 mL) anddried in vacuo to afford compound 528 (380 mg, 84%; HCl salt) as whitesolid. TLC: 40% EtOAc/hexanes (R_(f). 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ8.29 (br s, 3H), 7.84 (s, 1H), 7.82 (d, J=2.1 Hz, 1H), 6.70 (d, J=2.3Hz, 1H), 4.31 (s, 2H), 3.89 (s, 3H); LC-MS (Agilent 6310 Ion Trap):99.97%; 195.2 (M⁺+1); (column; X-Select HSS T3 (150×3 mm, 2.5 μm); RT0.62 min. 2.5 mM Aq. NH₄OAc:ACN; 0.6 mL/min).

Synthesis of tert-butyl (1-((5-(aminomethyl) thiazol-2-yl) methyl)piperidin-4-yl) carbamate (534)

Synthesis of tert-butyl (1-((5-(((tert-butyldimethylsilyl) oxy) methyl)thiazol-2-yl) methyl) piperidin-4-yl) carbamate (530)

To a stirring solution of 5-(((tert-butyldimethylsilyl) oxy) methyl)thiazole-2-carbaldehyde 495 (1.2 g, 4.66 mmol) in 1, 2-dichloroethane(50 mL) under inert atmosphere were added tert-butylpiperidin-4-ylcarbamate 529 (1.12 g, 5.60 mmol) and sodiumtriacetoxyborohydride (2.96 g, 14.00 mmol) at 0° C.; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with CH₂Cl₂ (200 mL),washed with water (100 mL) and brine (100 mL). The organic extract wasdried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 30% EtOAc/hexanes to afford compound 530 (800 mg,49%) as a pale yellow thick syrup. TLC: 20% EtOAc/hexanes (R_(f): 0.1);¹H NMR (DMSO-d₆, 500 MHz): δ 7.52 (s, 1H), 6.76 (br d, J=7.2 Hz, 1H),4.85 (s, 2H), 3.72 (s, 2H), 3.24-3.21 (m, 1H), 2.83-2.79 (m, 2H),2.14-2.07 (m, 2H), 1.70-1.66 (m, 2H), 1.47-1.39 (m, 11H), 0.86 (s, 9H),0.07 (s, 6H); LC-MS: 93.12%; 442.2 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 2.18 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl (1-((5-(hydroxymethyl) thiazol-2-yl) methyl)piperidin-4-yl) carbamate (531)

To a stirring solution of compound 530 (800 mg, 1.81 mmol) in THF (15mL) under inert atmosphere was added tetrabutylammonium fluoride (1.0 Msolution in THF, 2.72 mL, 2.72 mmol) at 0° C. and stirred at the sametemperature for 1 h. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was quenched with ice-cold water(100 mL) and extracted with EtOAc (2×75 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 4% MeOH/CH₂Cl₂ to afford compound 531 (650mg, quantitative) as thick syrup. TLC: 5% MeOH/CH₂Cl₂ (R_(f). 0.1);¹H-NMR (DMSO-d₆, 500 MHz): δ 7.48 (s, 1H), 6.77 (br d, J=6.7 Hz, 1H),5.46 (br t, J=5.5 Hz, 1H), 4.62 (br d, J=5.8 Hz, 2H), 3.71 (br s, 2H),3.03-3.01 (m, 1H), 2.84-2.80 (m, 2H), 2.14-2.08 (m, 2H), 1.75-1.54 (m,2H), 1.47-1.37 (m, 11H); LC-MS: 94.85%; 328.0 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.40 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (2-((4-((tert-butoxycarbonyl) amino) piperidin-1-yl)methyl) thiazol-5-yl) methyl methanesulfonate (532)

To a stirring solution of compound 531 (650 mg, 1.98 mmol) in CH₂Cl₂ (30mL) under inert atmosphere were added triethyl amine (1.43 mL, 9.93mmol) at 0° C. and stirred for 10 min. To this was added methanesulfonylchloride (453.2 mg, 3.97 mmol) at 0° C.; warmed to RT and stirred for 3h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was quenched with ice-cold water (2×50 mL) andextracted with CH₂Cl₂ (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to affordcrude compound 532 (600 mg) as pale brown liquid. The crude takenforward for next step with out further purification. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.4);

Synthesis of tert-butyl (1-((5-(azidomethyl) thiazol-2-yl) methyl)piperidin-4-yl) carbamate (533)

To a stirring solution of compound 532 (600 mg, 1.48 mmol) in DMF (10mL) under inert atmosphere was added sodium azide (284 mg, 4.44 mmol) atRT and stirred for 16 h. The reaction was monitored by TLC and LC-MS;after completion of the reaction, the reaction mixture was diluted withice-cold water (100 mL) and extracted with EtOAc (2×75 mL). The combinedorganic extracts were dried over sodium sulphate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel flash column chromatography using 70% EtOAc/hexanesto afford compound 533 (400 mg, 76%) as thick syrup. TLC: 70%EtOAc/hexanes (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 500 MHz): δ 7.67 (s, 1H),6.78 (br d, J=7.5 Hz, 1H), 4.69 (s, 2H), 3.76 (s, 2H), 3.28-3.19 (m,1H), 2.85-2.80 (m, 2H), 2.18-2.11 (m, 2H), 1.71-1.67 (m, 2H), 1.48-1.32(m, 11H); LC-MS: 92.56%; 353.0 (M⁺+1); (column; Ascentis Express C-18,(50×3.0 mm, 2.7 μm); RT 1.80 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min);

Synthesis of tert-butyl (1-((5-(aminomethyl) thiazol-2-yl) methyl)piperidin-4-yl) carbamate (534)

To a stirring solution of compound 533 (300 mg, 0.85 mmol) in THF:H₂O(4:1, 5 mL) was added triphenyl phosphine (446 mg, 1.70 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC and LC-MS; aftercompletion of the reaction, the volatiles were removed in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 4-5% MeOH/CH₂Cl₂ to afford compound 534 (250 mg,91%) as semi solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆,400 MHz): δ=7.43 (s, 1H), 3.86 (s, 1H), 3.69 (s, 1H), 3.30-3.12 (m, 3H),2.84-2.79 (m, 2H), 2.17-2.03 (m, 2H), 1.70-1.67 (m, 2H), 1.37 (s, 9H);LC-MS: 81.58%; 327.1 (M⁺+1); (column; Kinetex EVOC-18 (50×3.0 mm, 2.6μm); RT 1.60 min. 2.5 mM Aq. NH4OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH,0.8 mL/min).

Compound Preparation

Acids similar to compound 6 (compounds 13, 20, 32, 40, 47, 54, 61, 68,76, 81, 88, 149, 153, 155, 158, 200, 211, 216, 89, 92, 95, 105, 113,120, 126, 135, 143, 144, 163, 169, 172, 176, 185, 190, 194) weresynthesized as mentioned above and converted to final products eitherusing commercially available amines or prepared amines employing typicalprocedures A and B, and the results are captured in the Table 1:

Typical Procedure A:

To a stirring solution of compound 6 (100 mg, 0.36 mmol) in DMF (5 mL)under in inert atmosphere were added EDCI.HCl (105 mg, 0.55 mmol), HOBt(75 mg, 0.55 mmol), compound 255 (80 mg, 0.44 mmol) anddiisopropylethylamine (0.19 mL, 1.10 mmol) at 0° C. warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo to obtain the crude.The crude was either directly dried in vacuo or triturated or purifiedthrough silica gel column chromatography to afford the desired compound.

Typical Procedure B:

To a stirring solution of acid 105 (130 mg, 0.41 mmol) in DMF (6 mL)under inert atmosphere were added HATU (187 mg, 0.49 mmol) and stirredfor 10 min. To this were added and compound 255 (83 mg, 0.49 mmol) anddiisopropylethylamine (0.21 mL, 1.23 mmol) at 0° C. warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the diluted with water (10 mL) and extracted with 5%MeOH/CH₂Cl₂ (2×10 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was either directly dried in vacuo or triturated or purifiedthrough silica gel column chromatography or preparative HPLCpurification to afford the desired compound.

TABLE 1 Synthesis from compound 13, 20, 32, 40, 47, 54, 61, 68, 76, 81,88, 149, 153, 155, 158, 200, 211, 216, 89, 92, 95, 105, 113, 120, 126,135, 143, 144, 163, 169, 172, 176, 185, 190, 194 and various commericaland synthesized amines. Procedure, Interemediate, Rx. Yield Mass Spec.Mass Spec. Example Structure amine (%) Found Calculated ¹H-NMR  1421

A, 6, 255 21 435.9 (M⁺ + 1); 435.03 for C₁₉H₁₂F₃N₃O₂S₂ 1H-NMR (DMSO-d6,400 MHz): δ 10.77 (s, 1H), 9.38 (t, J = 5.7 Hz, 1H), 8.05 (s, 1H), 7.72-7.66 (m, 3H), 7.60 (dd, J = 8.0, 1.8 Hz, 1H), 7.53 (td, J = 7.1, 1.6 Hz,1H), 7.50-7.43 (m, 2H), 4.72 (d, J = 5.6 Hz, 2H);  1431

A, 6, 263 23 435.9 (M⁺ + 1); 435.03 for C₁₉H₁₂F₃N₃O₂S₂ 1H-NMR (DMSO-d6,400 MHz): δ 10.80 (s, 1H), 9.45 (t, J = 5.3 Hz, 1H), 9.09 (s, 1H), 7.70(d, J = 8.0 Hz, 3H), 7.64-7.43 (m, 4H), 4.77 (d, J = 4.8 Hz, 2H);  1424

A, 6, 242 53 396.9 (M⁺ + 1); C₁₉H₁₆N₄O₂S₂ 396.07 1H NMR (DMSO- d6, 500MHz): δ 10.77 (s, 1H), 9.03 (t, J = 5.6 Hz, 1H), 7.69-7.62 (m, 3H),7.59-7.42 (m, 4H), 7.34-7.30 (m, 1H), 6.87 (s, 1H), 4.36 (d, J = 5.8 Hz,2H), 2.72 (d, J = 4.9 Hz, 3H);  1425

A, 6, 245 61 411.0 (M⁺ + 1); C₂₀H₁₈N₄O₂S₂ 410.09 ¹H NMR (DMSO-d₆, 400MHz): δ 10.75 (s, 1H), 9.05 (t, J = 5.7 Hz, 1H), 7.72- 7.62 (m, 3H),7.59- 7.42 (m, 4H), 6.99 (s, 1H), 4.41 (d, J = 5.5 Hz, 2H), 2.95 (s,6H);  1473

A, 92, 220 18 419.8 (M⁺ + 1); C₁₇H₁₀ClN₃O₄S₂ 418.98 1H NMR (DMSO- d6,400 MHz): δ 13.19 (br s, 1H), 11.62 (s, 1H), 8.10 (d, J = 8.2 Hz, 1H),8.07-7.97 (m, 4H), 7.95-7.85 (m, 2H), 7.63 (s, 1H);  1496

A, 13, 217 34 381.9 (M⁺ + 1) C₁₉H₁₅N₃O₂S₂ 381.06 1H NMR (DMSO- d6, 400MHz): δ 10.63 (s, 1H), 9.00- 8.95 (m, 2H), 7.79 (s, 1H), 7.66 (dd, J =7.5, 1.5 Hz, 1H), 7.54-7.41 (m, 4H), 7.15 (s, 1H), 4.61 (d, J = 5.7 Hz,2H), 2.23 (s, 3H);  1549

A, 6, 271 21 396.0 (M⁺ + 1); 395.08 for C₂₀H₁₇N₃O₂S₂ ¹H NMR (DMSO-d₆,400 MHz): 10.72 (s, 1H), 8.87 (s, 1H), 8.62 (s, 1H), 7.72- 7.60 (m, 4H),7.58- 7.42 (m, 4H), 1.74 (s, 6H);  1555

A, 6, 277 38 424.0 (M⁺ + 1); 423.11 for C₂₂H₂₁N₃O₂S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.78 (s, 1H), 9.19 (t, J = 5.6 Hz, 1H), 7.72- 7.64 (m, 3H),7.59 (dd, J = 8.2, 1.9 Hz, 1H), 7.56-7.51 (m, 2H), 7.50-7.43 (m, 2H),4.57 (d, J = 5.6 Hz, 2H), 1.32 (s, 9H);  1556

A, 6, 285 38 461.9 (M⁺ + 1); 461.07 for C₂₄H₁₆FN₃O₂S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.78 (s, 1H), 9.28 (t, J = 5.3 Hz, 1H), 7.93 (dd, J = 8.9,5.3 Hz, 2H), 7.78 (s, 1H), 7.73- 7.65 (m, 3H), 7.60 (dd, J = 8.3, 1.8Hz, 1H), 7.56-7.43 (m, 3H), 7.31 (t, J = 8.9 Hz, 2H), 4.65 (d, J = 5.6Hz, 2H);  1598

A, 6, 304 48 452.9 (M⁺ + 1); 452.10 for C₂₂H₂₀N₄O₃S₂ ¹H-NMR (DMSO-d₆,500 MHz): δ 10.76 (s, 1H), 9.08 (t, J = 5.5 Hz, 1H), 7.70-7.63 (m, 3H),7.60-7.42 (m, 4H), 7.05 (s, 1H), 4.42 (d, J = 5.5 Hz, 2H), 3.68-3.64 (m,4H), 3.35-3.25 (m, 4H);  1604

A, 6, 288 39 471.2 (M⁺ + 1); 470.09 for C₂₂H₂₂N₄O₂S₃ ¹H-NMR (DMSO-d₆,500 MHz): δ 10.77 (s, 1H), 9.20 (t, J = 5.6 Hz, 1H), 7.72-7.64 (m, 3H),7.59-7.43 (m, 5H), 4.54 (d, J = 5.5 Hz, 2H), 3.27 (t, J = 6.9 Hz, 2H),2.56 (t, J = 6.8 Hz, 2H), 2.16 (s, 6H);  1605

A, 6, 357 38 459.9 (M⁺ + 1); 459.07 for C₂₄H₁₇N₃O₃S₂ ¹H-NMR (DMSO-d₆,500 MHz): δ 10.77 (s, 1H), 9.94 (s, 1H), 9.24 (t, J = 5.8 Hz, 1H), 7.72-7.65 (m, 5H), 7.62-7.43 (m, 5H), 6.83 (d, J = 8.7 Hz, 2H), 4.62 (d, J =5.5 Hz, 2H);  1606

A, 6, 363 49 473.9 (M⁺ + 1); 473.09 for C₂₅H₁₉N₃O₃S₂ ¹H-NMR (DMSO-d₆,500 MHz): δ 10.78 (s, 1H), 9.25 (t, J = 5.6 Hz, 1H), 7.81 (d, J = 8.7Hz, 2H), 7.73-7.65 (m, 4H), 7.63-7.43 (m, 4H), 7.02 (d, J = 8.7 Hz, 2H),4.63 (d, J = 5.5 Hz, 2H), 3.80 (s, 3H);  1608

A, 6, 360 23 531.0 (M⁺ + 1); 530.14 for C₂₈H₂₆N₄O₃S₂ ¹H NMR (DMSO-d₆,500 MHz): δ 10.77 (s, 1H), 9.28 (t, J = 5.1 Hz, 1H), 7.78 (d, J = 8.7Hz, 2H), 7.72-7.59 (m, 5H), 7.55- 7.41 (m, 3H), 7.01 (d, J = 8.7 Hz,2H), 4.62 (d, J = 5.5 Hz, 2H), 4.10 (t, J = 5.6 Hz, 2H), 2.67 (t, J =5.2 Hz, 2H), 2.24 (s, 6H);  1627

A, 6, 282 26 393.0 (M⁺ + 1); 392.04 for C₁₉H₁₂N₄O₂S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.77 (br s, 1H), 9.38 (t, J = 4.8 Hz, 1H), 8.12 (s, 1H),7.72- 7.65 (m, 3H), 7.63-7.42 (m, 4H), 4.72 (d, J = 5.4 Hz, 2H);  1758

A, 13, 357 22 474.0 (M⁺ + 1); 473.09 for C₂₅H₁₉N₃O₃S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.63 (s, 1H), 9.97 (br s, 1H), 8.98 (t, J = 5.9 Hz, 1H),7.72 (d, J = 8.8 Hz, 2H), 7.68- 7.64 (m, 2H), 7.54-7.42 (m, 4H), 7.16(s, 1H), 6.85 (d, J = 8.7 Hz, 2H), 4.58 (d, J = 5.8 Hz, 2H), 2.25 (s,3H);  1910

B^(a), 105, 255 10 482.1 (M⁺ + 1); 481.04 for C₂₀H₁₄F₃N₃O₄S₂ ¹H NMR (400MHz, DMSO-d₆): δ 11.35 (s, 1H), 9.28-9.26 (m, 1H), 8.06 (s, 1H),7.99-7.94 (m, 2H), 7.91-7.81 (m, 3H), 7.32 (s, 1H), 4.73 (d, J = 4.0 Hz,2H), 2.32 (s, 3H);  1911

A, 105, 227 13 515.1 (M⁺ + 1); 514.08 for C₂₆H₁₈N₄O₄S₂ ¹H NMR (400 MHz,DMSO-d₆): δ 11.35 (s, 1H), 9.21 (t, J = 5.9 Hz, 1H), 8.09 (d, J = 8.5Hz, 2H), 7.99-7.93 (m, 4H), 7.92-7.81 (m, 4H), 7.32 (s, 1H), 4.69 (d, J= 5.9 Hz, 2H), 2.34 (s, 3H);  1915

A, 32 227 52 561.0 (M⁺ + 1); 560.00 for C₂₆H₁₇BrN₄O₂S₂ 1H-NMR (DMSO- d6,400 MHz): δ 10.39 (s, 1H), 9.18 (t, J = 5.3 Hz, 1H), 8.09 (d, J = 8.0Hz, 2H), 7.98-7.88 (m, 3H), 7.71-7.66 (m, 1H), 7.59- 7.44 (m, 4H), 4.65(d, J = 5.0 Hz, 2H), 2.25 (s, 3H); 11106-A

A, 92, 517 40 661.1 (M⁺ + 1) 660.17 for C₃₃H₃₂N₄O₇S₂ ¹H NMR (500 MHz,DMSO- d₆): δ 11.51 (s, 1H), 9.44 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.1Hz, 1H), 8.01-7.96 (m, 2H), 7.93-7.77 (m, 6H), 7.72 (s, 1H), 7.00 (d, J= 8.7 Hz, 2H), 4.66 (d, J = 5.8 Hz, 2H), 4.05 (t, J = 6.1 Hz, 2H), 3.56(s, 3H), 3.21-3.18 (m, 1H), 3.06-2.99 (m, 1H), 2.82-2.74 (m, 1H), 2.56-2.52 (m, 1H), 2.39-2.34 (m, 1H), 2.07-1.98 (m, 1H), 1.88-1.70 (m, 5H); 1914

A, 32, 255 94 528.3 (M⁺ + 1); 526.96 for C₂₀H₁₃BrF₃N₃O₂S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 10.39 (s, 1H), 9.24 (t, J = 5.6 Hz, 1H), 8.05 (s,1H), 7.71-7.66 (m, 1H), 7.61-7.44 (m, 4H), 4.68 (d, J = 5.6 Hz, 2H),2.23 (s, 3H);  1535

A, 20, 297 69 395.8 (M⁺ + 1); 395.08 for C₂₀H₁₇N₃O₂S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.24 (s, 1H), 8.96 (t, J = 6.0 Hz, 1H), 7.67-7.63 (m, 1H),7.55- 7.40 (m, 5H), 7.05 (d, J = 7.8 Hz, 1H), 4.51 (d, J = 5.9 Hz, 2H),2.59 (s, 3H), 2.27 (s, 3H);  1755

A, 20, 357  9 474.1 (M⁺ + 1); 473.09 for C₂₅H₁₉N₃O₃S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.24 (s, 1H), 9.96 (s, 1H), 9.01 (t, J = 5.8 Hz, 1H), 7.72(d, J = 8.5 Hz, 2H), 7.67-7.62 (m, 2H), 7.54-7.40 (m, 4H), 7.08 (d, J =8.0 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 4.58 (d, J = 5.6 Hz, 2H), 2.29(s, 3H);  1766

A, 20, 255 41 448.1 (M⁺ − 1); 449.05 for C₂₀H₁₄F₃N₃O₂S₂ ¹H-NMR (DMSO-d₆,500 MHz): δ 10.24 (s, 1H), 9.15 (t, J = 5.8 Hz, 1H), 8.04 (s, 1H),7.67-7.63 (m, 1H), 7.54-7.49 (m, 2H), 7.48-7.41 (m, 2H), 7.11 (d, J =7.8 Hz, 1H), 4.69 (d, J = 5.8 Hz, 2H), 2.28 (s, 3H);  1767

A, 95, 255 26 481.9 (M⁺ + 1); 481.04 for C₂₀H₁₄F₃N₃O₄S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.86 (br s, 1H), 9.30 (t, J = 5.8 Hz, 1H), 8.06 (s, 1H),7.95-7.84 (m, 4H), 7.80 (td, J = 7.5, 1.4 Hz, 1H), 7.38 (d, J = 8.2 Hz,1H), 4.72 (d, J = 5.6 Hz, 2H), 2.31 (s, 3H);  1752

A, 54, 357  7 477.9 (M⁺ + 1); 477.06 for C₂₄H₁₆FN₃O₃S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.97 (br s, 1H), 9.95 (s, 1H), 9.27 (t, J = 5.5 Hz, 1H),7.73-7.65 (m, 5H), 7.61 (dd, J = 8.3, 1.9 Hz, 1H), 7.52-7.46 (m, 1H),7.40 (d, J = 7.4 Hz, 1H), 7.34-7.28 (m, 1H), 6.82 (d, J = 8.7 Hz, 2H),4.62 (d, J = 5.5 Hz, 2H);  1746

A, 61, 357  9 477.9 (M⁺ + 1); 477.06 for C₂₄H₁₆FN₃O₃S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.91 (s, 1H), 9.94 (s, 1H), 9.25 (br t, J = 5.6 Hz, 1H),7.76-7.31 (m, 9H), 6.83 (d, J = 8.7 Hz, 2H), 4.62 (br d, J = 5.6 Hz,2H);  1747

A, 68, 357  9 477.9 (M⁺ + 1); 477.06 for C₂₄H₁₆FN₃O₃S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.80 (s, 1H), 9.92 (br s, 1H), 9.23 (t, J = 5.4 Hz, 1H),7.76-7.57 (m, 7H), 7.43 (dd, J = 2.3, 8.4, 2.3 Hz, 1H), 7.30 (td, J =8.5, 2.4 Hz, 1H), 6.80 (d, J = 8.5 Hz, 2H), 4.60 (d, J = 5.4 Hz, 2H); 1753

A, 76, 357 12 477.9 (M⁺ + 1); 477.06 for C₂₄H₁₆FN₃O₃S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.90 (s, 1H), 9.95 (s, 1H), 9.26 (t, J = 5.5 Hz, 1H),7.74-7.59 (m, 6H), 7.54-7.44 (m, 3H), 6.83 (d, J = 8.6 Hz, 2H), 4.62 (d,J = 5.5 Hz, 2H);  1904

A^(c), 144, 227 51 519.0 (M⁺ + 1); 518.05 for C₂₅H₁₅FN₄O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 1.58 (br s, 1H), 9.54 (t, J = 5.6 Hz, 1H), 8.13(d, J = 8.7 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.8 Hz, 3H),7.90-7.82 (m, 3H), 7.73 (d, J = 7.4 Hz, 1H), 7.70- 7.64 (m, 1H), 4.72(br d, J = 5.6 Hz, 2H);  1749

A, 81, 357 14 477.9 (M⁺ + 1); 477.06 for C₂₄H₁₆FN₃O₃S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.72 (s, 1H), 9.96 (s, 1H), 9.04 (t, J = 5.3 Hz, 1H),7.73-7.64 (m, 4H), 7.60-7.43 (m, 5H), 6.84 (d, J = 8.7 Hz, 2H), 4.61 (d,J = 5.8 Hz, 2H);  1750

A, 88, 357 10 495.9 (M⁺ + 1); 495.05 for C₂₄H₁₅F₂N₃O₃S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.65 (br s, 1H), 9.96 (br s, 1H), 9.39 (t, J = 5.8 Hz, 1H),7.74-7.64 (m, 4H), 7.58-7.46 (m, 4H), 6.85 (d, J = 8.7 Hz, 2H), 4.63 (d,J = 5.6 Hz, 2H);  1541

A, 40, 297 59 415.9 (M⁺ + 1); 415.02 for C₂₉H₁₄ClN₃O₂S₂ ¹H NMR (DMSO-d₆,400 MHz): δ 10.91 (s, 1H), 9.20 (t, J = 5.9 Hz, 1H), 7.71-7.64 (m, 3H),7.62- 7.55 (m, 3H), 7.49 (s, 1H), 4.55 (d, J = 5.7 Hz, 2H), 2.57 (s,3H);  1760

A^(d), 40, 357 12 493.9 (M⁺ + 1); 493.03 for C₂₄H₁₆ClN₃O₃S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 10.93 (br s, 1H), 9.95 (br s, 1H), 9.27 (t, J =5.7 Hz, 1H), 7.74- 7.60 (m, 7H), 7.57 (s, 2H), 6.83 (d, J = 8.7 Hz, 2H),4.62 (d, J = 5.6 Hz, 2H);  1544

A, 47, 297 57 415.9 (M⁺ + 1); 415.02 for C₁₉H₁₄ClN₃O₂S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.86 (s, 1H), 9.20 (t, J = 5.7 Hz, 1H), 7.71-7.64 (m, 4H),7.62- 7.58 (m, 1H), 7.54 (dd, J = 8.4, 2.1 Hz, 1H), 7.49 (s, 1H), 4.55(d, J = 5.7 Hz, 2H), 2.57 (s, 3H);  1761

A, 47, 357 12 494.0 (M⁺ + 1); 493.03 for C₂₄H₁₆ClN₃O₃S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.86 (s, 1H), 9.94 (s, 1H), 9.25 (t, J = 5.9 Hz, 1H), 7.71(dd, J = 6.4, 1.8 Hz, 2H), 7.68 (s, 2H), 7.67-7.60 (m, 4H), 7.53 (dd, J= 8.3, 2.1 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 4.62 (d, J = 5.6 Hz, 2H); 1772

A^(a), 89, 255 54 451.9 (M⁺ + 1); 451.03 for C₁₉H₁₂F₃N₃O₃S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.06 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.05 (s,1H), 7.88 (dd, J = 8.2, 1.5 Hz, 1H), 7.84-7.77 (m, 2H), 7.76-7.68 (m,3H), 7.63 (td, J = 7.5, 1.3 Hz, 1H), 4.72 (d, J = 5.6 Hz, 2H);  1526

A, 89, 297 21 397.9 (M⁺ + 1); 397.06 for C₁₉H₁₅N₃O₃S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.05 (s, 1H), 9.26 (t, J = 5.7 Hz, 1H), 7.85 (dd, J = 8.3,1.5 Hz, 1H), 7.80 (dd, J = 7.6, 3.9 Hz, 2H), 7.76-7.67 (m, 3H), 7.63(td, J = 8.4, 1.1 Hz, 1H), 7.49 (s, 1H), 4.56 (d, J = 5.7 Hz, 2H), 2.56(s, 3H);  1528

A, 92, 297 33 413.9 (M⁺ + 1); 413.05 for C₁₉H₁₅N₃O₄S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.50 (br s, 1H), 9.37 (t, J = 5.7 Hz, 1H), 8.05 (d, J = 8.3Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.82 (m, 3H), 7.78 (dd, J = 8.3, 1.4Hz, 1H), 7.50 (s, 1H), 4.58 (d, J = 5.6 Hz, 2H), 2.57 (s, 3H);  1529

A, 92, 230 22 414.9 (M⁺ + 1); 414.05 for C₁₈H₁₄N₄O₄S₂ ¹H-NMR (DMSO-d₆,400 MHz): 11.49 (br s, 1H), 9.18 (t, J = 5.4 Hz, 1H), 8.03 (d, J = 8.3Hz, 1H), 7.98 (td, J = 7.3, 1.0 Hz, 2H), 7.93-7.81 (m, 3H), 7.77 (dd, J= 8.3, 1.3 Hz, 1H), 6.80 (s, 1H), 6.79 (br s, 2H), 4.38 (d, J = 5.5 Hz,2H);  1525

A, 92, 291 32 475.9 (M⁺ + 1); 475.07 for C₂₄H₁₇N₃O₄S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.52 (s, 1H), 9.47 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.3Hz, 1H), 7.98 (td, J = 7.6, 1.0 Hz, 2H), 7.93-7.79 (m, 7H), 7.54-7.39(m, 3H), 4.69 (d, J = 5.6 Hz, 2H);  1550

A, 92, 277 26 455.9 (M⁺ + 1); 455.10 for C₂₂H₂₁N₃O₄S₂ ¹H-NMR (DMSO-d₆,500 MHz): δ 11.50 (s, 1H), 9.38 (t, J = 5.8 Hz, 1H), 8.05 (d, J = 8.4Hz, 1H), 8.00-7.96 (m, 2H), 7.90 (td, J = 7.4, 1.3 Hz, 1H), 7.88-7.83(m, 2H), 7.80 (dd, J = 8.2, 1.3 Hz, 1H), 7.54 (s, 1H), 4.60 (d, J = 5.8Hz, 2H), 1.33 (s, 9H);  1551

A, 92, 239 42 427.9 (M⁺ + 1); 427.07 for C₂₀H₁₇N₃O₄S₂ ¹H-NMR (DMSO-d₆,500 MHz): δ 11.52 (s, 1H), 9.40 (t, J = 5.8 Hz, 1H), 8.04 (d, J = 8.4Hz, 1H), 7.97 (t, J = 8.4 Hz, 2H), 7.90 (t, J = 7.1 Hz, 1H), 7.87-7.81(m, 2H), 7.78 (d, J = 8.1 Hz, 1H), 7.53 (s, 1H), 4.58 (d, J = 5.8 Hz,2H), 2.89 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H);  1552

A, 92, 251 34 441.9 (M⁺ + 1); 441.08 for C₂₁H₁₉N₃O₄S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.50 (s, 1H), 9.38 (t, J = 5.8 Hz, 1H), 8.05 (d, J = 8.3Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.82 (m, 3H), 7.79 (dd, J = 8.3, 1.6Hz, 1H), 7.54 (s, 1H), 4.60 (d, J = 5.7 Hz, 2H), 3.24-3.15 (m, 1H), 1.27(d, J = 6.9 Hz, 6H);  1553

A, 92, 255 16 468.3 (M⁺ + 1); 467.02 for C₁₉H₁₂F₃N₃O₄S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.50 (s, 1H), 9.56 (t, J = 5.6 Hz, 1H), 8.08- 8.04 (m, 2H),7.98 (td, J = 7.7, 0.9 Hz, 2H), 7.94-7.83 (m, 3H), 7.81 (dd, J = 8.2,1.4 Hz, 1H), 4.75 (d, J = 5.5 Hz, 2H);  1566

A, 92, 285 34 486.9 (M⁺ + 1); 486.10 for C₂₇H₁₉FN₂O₄S ¹H-NMR (DMSO-d₆,400 MHz): δ 11.52 (s, 1H), 9.31 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.5Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.82 (m, 4H), 7.66 (dd, J = 8.8, 5.5Hz, 2H), 7.59-7.56 (m, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.6Hz, 1H), 7.32-7.25 (m, 3H), 4.54 (d, J = 5.9 Hz, 2H);  1584

A, 92, 360 47 563.0 (M⁺ + 1); 562.13 for C₂₈H₂₆N₄O₅S₂ ¹H NMR (DMSO-d₆,400 MHz): δ 11.52 (br s, 1H), 9.47 (t, J = 5.4 Hz, 1H), 8.05 (d, J = 8.3Hz, 1H), 7.98 (td, J = 7.5, 1.0 Hz, 2H), 7.90 (td, J = 7.4, 1.3 Hz, 1H),7.87-7.82 (m, 3H), 7.80 (d, J = 8.9 Hz, 2H), 7.72 (s, 1H), 7.02 (d, J =8.8 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.09 (t, J = 5.8 Hz, 2H), 2.63(t, J = 5.8 Hz, 2H), 2.21 (s, 6H);  1595

A, 92, 357 50 492.0 (M⁺ + 1); 491.06 for C₂₄H₁₇N₃O₅S₂ ¹H NMR (DMSO-d₆,500 MHz): δ 11.51 (s, 1H), 9.94 (s, 1H), 9.43 (t, J = 5.8 Hz, 1H), 8.05(d, J = 8.4 Hz, 1H), 8.00-7.96 (m, 2H), 7.90 (td, J = 7.5, 1.2 Hz, 1H),7.87-7.83 (m, 2H), 7.81 (dd, J = 8.2, 1.3 Hz, 1H), 7.71-7.67 (m, 3H),6.83 (d, J = 8.4 Hz, 2H), 4.65 (d, J = 5.5 Hz, 2H);  1596

A, 92, 363 60 506.0 (M⁺ + 1); 505.08 for C₂₅H₁₉N₃O₅S₂ ¹H NMR (DMSO-d₆,500 MHz): δ 11.51 (s, 1H), 9.45 (t, J = 5.6 Hz, 1H), 8.06 (d, J = 8.4Hz, 1H), 7.98 (t, J = 8.5 Hz, 2H), 7.93-7.78 (m, 6H), 7.72 (s, 1H), 7.02(d, J = 9.0 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 3.80 (s, 3H);  1587

A, 92, 372 58 605.0 (M⁺ + 1); 604.15 for C₃₀H₂₈N₄O₆S₂ ¹H NMR (DMSO-d₆,400 MHz): δ 11.51 (s, 1H), 9.44 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.2Hz, 1H), 8.00-7.96 (m, 2H), 7.90 (td, J = 7.5, 1.5 Hz, 1H), 7.87-7.77(m, 5H), 7.72 (s, 1H), 7.03 (d, J = 8.9 Hz, 2H), 4.66 (d, J = 5.6 Hz,2H), 4.14 (t, J = 5.7 Hz, 2H), 3.59-3.55 (m, 4H), 2.70 (t, J = 5.7 Hz,2H), 2.48-2.46 (m, 4H);  1590

A, 92, 288 36 502.9 (M⁺ + 1); 502.08 for C₂₂H₂₂N₄O₄S₃ ¹H-NMR (DMSO-d₆,500 MHz): δ 11.50 (br s, 1H), 9.39 (t, J = 5.5 Hz, 1H), 8.04 (d, J = 8.4Hz, 1H), 7.97 (t, J = 8.1 Hz, 2H), 7.93-7.75 (m, 4H), 7.57 (s, 1H), 4.57(d, J = 5.8 Hz, 2H), 3.29- 3.25 (m, 2H), 2.55 (t, J = 6.9 Hz, 2H), 2.15(s, 6H);  1628

A, 92, 282 20 424.9 (M⁺ + 1); 424.03 for C₁₉H₁₂N₄O₄S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.53 (s, 1H), 9.59 (t, J = 5.4 Hz, 1H), 8.14 (s, 1H), 8.07(d, J = 8.3 Hz, 1H), 7.98 (t, J = 7.3 Hz, 2H), 7.94-7.83 (m, 3H), 7.80(d, J = 8.3 Hz, 1H), 7.82-7.78 (m, 1H), 4.76 (d, J = 5.5 Hz, 2H);  1645

A, 92, 312 40 519.0 (M⁺ + 1); 518.11 for C₂₆H₂₂N₄O₄S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.51 (s, 1H), 9.41 (t, J = 5.6 Hz, 1H), 8.05 (d, J = 8.4Hz, 1H), 7.98 (t, J = 8.7 Hz, 2H), 7.90 (t, J = 7.1 Hz, 1H), 7.87-7.79(m, 3H), 7.68 (d, J = 9.0 Hz, 2H), 7.63 (s, 1H), 6.74 (d, J = 9.0 Hz,2H), 4.63 (d, J = 5.8 Hz, 2H), 2.96 (s, 6H);  1648

A, 92, 307 21 498.0 (M⁺ + 1); 497.12 for C₂₃H₂₃N₅O₄S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.50 (s, 1H), 9.27 (t, J = 5.7 Hz, 1H), 8.07- 7.75 (m, 7H),7.04 (s, 1H), 4.44 (d, J = 5.6 Hz, 2H), 3.33-3.31 (m, 4H), 2.40- 2.34(m, 4H), 2.19 (s, 3H);  1650

A, 92, 218 35 399.9 (M⁺ + 1); 399.03 for C₁₈H₁₃N₃O₄S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.53 (br s, 1H), 9.66-9.58 (m, 1H), 8.08 (d, J = 8.2 Hz,1H), 8.02-7.96 (m, 2H), 7.94- 7.82 (m, 4H), 7.73 (d, J = 3.2 Hz, 1H),7.63 (d, J = 3.3 Hz, 1H), 4.75 (d, J = 6.1 Hz, 2H);  1679

A, 92, 367 24 577.1 (M⁺ + 1); 576.15 for C₂₉H₂₈N₄O₅S₂ ¹H NMR (DMSO-d₆,400 MHz): δ 11.52 (br s, 1H), 9.44 (t, J = 5.7 Hz, 1H), 8.05 (d, J = 8.3Hz, 1H), 8.00-7.95 (m, 2H), 7.93- 7.84 (m, 3H), 7.83-7.77 (m, 3H), 7.72(s, 1H), 7.00 (d, J = 8.9 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.04 (t, J= 6.4 Hz, 2H), 2.34 (t, J = 7.1 Hz, 2H), 2.13 (s, 6H), 1.89-1.80 (m,2H);  1763

A, 92, 219 89 427.9 (M⁺ + 1); 427.07 for C₂₀H₁₇N₃O₄S₂ 1H-NMR (DMSO-d6,400 MHz): δ 11.50 (br s, 1H), 9.29 (t, J = 5.6 Hz, 1H), 8.04 (d, J = 8.3Hz, 1H), 7.98 (td, J = 7.5, 0.9 Hz, 2H), 7.93-7.75 (m, 4H), 4.49 (d, J =5.6 Hz, 2H), 2.50 (s, 3H), 2.30 (s, 3H);  1814

A^(b), 92, 316 88 519.1 (M⁺ + 1); 518.05 for C₂₅H₁₅FN₄O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.47 (br s, 1H), 9.53 (t, J = 5.7 Hz, 1H), 8.35(t, J = 7.9 Hz, 1H), 8.11-7.95 (m, 5H), 7.93- 7.79 (m, 5H), 4.75 (d, J =5.6 Hz, 2H);  1661

A, 92, 369 24 505.9 (M⁺ + 1); 505.08 for C₂₅H₁₉N₃O₅S₂ ¹H-NMR (DMSO-d₆,500 MHz) (rotamers): δ 11.44 (br s, 1H), 10.00 (br s, 1H), 8.04-7.96 (m,3H), 7.94- 7.82 (m, 2H), 7.81-7.71 (m, 3H), 7.49-7.38 (m, 2H), 6.86 (d,J = 8.4 Hz, 2H), 4.82, 4.59 (s, 2H), 2.95, 2.76 (s, 3H);  1821

A^(b), 92, 319 29 531.1 (M⁺ + 1); 530.07 for C₂₆H₁₈N₄O₅S₂ ¹H-NMR(DMSO-d₆, 500 MHz): δ 11.52 (s, 1H), 10.60 (s, 1H), 9.45 (t, J = 5.3 Hz,1H), 8.06 (d, J = 8.2 Hz, 1H), 8.01-7.94 (m, 2H), 7.93-7.79 (m, 5H),7.72 (d, J = 3.5 Hz, 3H), 6.88 (d, J = 8.3 Hz, 1H), 4.66 (d, J = 5.1 Hz,2H), 3.54 (s, 2H);  1823-A

A^(c), 92, 326 32 520.1 (M⁺ + 1); 519.09 for C₂₆H₂₁N₃O₅S₂ ¹H NMR(DMSO-d₆, 500 MHz): δ 11.48 (br s, 1H), 9.35 (t, J = 5.5 Hz, 1H), 8.03(d, J = 8.4 Hz, 1H), 7.97 (t, J = 8.1 Hz, 2H), 7.92-7.80 (m, 3H), 7.76(d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.87 (d, J= 8.7 Hz, 2H), 4.56 (d, J = 5.8 Hz, 2H), 4.16 (s, 2H), 3.71 (s, 3H); 1840

A, 92, 338 19 548.1 (M⁺ + 1); 547.12 for C₂₈H₂₅N₃O₅S₂ ¹H NMR (400 MHz,DMSO- d₆) δ 11.52 (s, 1H), 9.49 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.3Hz, 1H), 7.98 (td, J = 7.8, 1.3 Hz, 2H), 7.93- 7.79 (m, 5H), 7.50 (dd, J= 7.5, 0.9 Hz, 1H), 7.45-7.37 (m, 2H), 7.34-7.29 (m, 1H), 5.00 (s, 1H),4.70 (d, J = 5.6 Hz, 2H), 3.07 (s, 2H), 0.99 (s, 6H);  1882

A^(b), 92, 345 29 483.0 (M⁺ + 1); 482.02 for C₂₁H₁₄N₄O₄S₃ ¹H NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.50 (t, J = 5.6 Hz, 1H), 8.06 (d,J = 8.4 Hz, 1H), 8.01-7.94 (m, 3H), 7.93-7.78 (m, 6H), 4.70 (d, J = 5.6Hz, 2H);  1906

A^(c), 92, 488  9 497.0 (M⁺ + 1); 496.09 for C₂₃H₂₀N₄O₅S₂ ¹H NMR (400MHz, DMSO- d₆): δ 11.51 (s, 1H), 9.33 (t, J = 5.8 Hz, 1H), 8.05 (d, J =8.3 Hz, 1H), 8.00-7.96 (m, 2H), 7.93-7.83 (m, 3H), 7.79 (dd, J = 8.3,1.6 Hz, 1H), 7.13 (s, 1H), 4.47 (d, J = 5.6 Hz, 2H), 3.74 (t, J = 6.2Hz, 4H), 2.48-2.45 (m, 4H);  1973

A, 92, 492 48 512.1 (M⁺ + 1); 511.10 for C₂₃H₂₁N₅O₅S₂ ¹H NMR (400 MHz,DMSO- d₆): δ 11.51 (s, 1H), 9.28 (t, J = 5.8 Hz, 1H), 8.04 (d, J = 8.3Hz, 1H), 8.01-7.95 (m, 2H), 7.94-7.83 (m, 3H), 7.79 (dd, J = 8.3, 1.5Hz, 1H), 7.67 (t, J = 5.3 Hz, 1H), 7.03 (s, 1H), 4.45 (d, J = 5.5 Hz,2H), 3.65-3.53 (m, 4H), 3.34-3.39 (m, 2H), 3.23-3.17 (m, 2H);  1927

A, 92, 500 40 499.0 (M⁺ + 1); 498.10 for C₂₃H₂₂N₄O₅S2 ¹H-NMR (DMSO-d₆,400 MHz): δ 11.51 (s, 1H), 9.39 (t, J = 5.6 Hz, 1H), 8.05 (br d, J = 8.2Hz, 1H), 7.98 (t, J = 7.0 Hz, 2H), 7.93-7.77 (m, 4H), 7.57 (s, 1H), 4.61(br d, J = 4.9 Hz, 2H), 3.73 (s, 2H), 3.59-3.54 (m, 4H), 2.47-2.43 (m,4H);  1885-A

A, 92, 534 25 612.1 (M⁺ + 1); 611.19 for C₂₉H₃₃N₅O₆S₂ 1H NMR (DMSO-d6,400 MHz): δ 11.50 (s, 1H), 9.38 (t, J = 5.7 Hz, 1H), 8.05 (d, J = 8.3Hz, 1H), 7.98 (dt, J = 7.5, 1.0 Hz, 2H), 7.94-7.82 (m, 3H), 7.79 (dd, J= 8.3, 1.5 Hz, 1H), 7.55 (s, 1H), 6.74 (d, J = 7.5 Hz, 1H), 4.60 (d, J =5.6 Hz, 2H), 3.69 (s, 2H), 3.26-3.08 (m, 2H), 2.84-2.75 (m, 2H),2.15-2.04 (m, 2H), 1.74-1.60 (m, 2H), 1.43-1.33 (m, 11H);  1929

A^(c), 92, 332 19 503.7 (M⁺ + 1); 503.06 for C₂₅H₁₇N₃O₅S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.57 (t, J = 5.8 Hz, 1H), 8.36-8.30(m, 2H), 8.12 (s, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 7.5, 1.1Hz, 2H), 7.93- 7.80 (m, 4H), 7.74-7.69 (m, 1H), 7.61-7.53 (m, 2H), 4.78(d, J = 5.6 Hz, 2H);  1957

A^(c), 92, 508 26 467.0 (M⁺ + 1); 466.04 for C₂₁H₁₄N₄O₅S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.51 (br t, J = 5.5 Hz, 1H), 8.55(s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.77 (m, 6H),4.70 (br d, J = 5.5 Hz, 2H);  1958

A^(c), 92, 512 48 466.9 (M⁺ + 1); 466.04 for C₂₁H₁₄N₄O₅S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.52 (t, J = 5.7 Hz, 1H), 8.31 (s,1H), 8.06 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 7.4, 1.0 Hz, 2H), 7.95-7.88(m, 2H), 7.87-7.79 (m, 3H), 7.45 (s, 1H), 4.72 (d, J = 5.6 Hz, 2H); 1991

A^(c), 92, 408 44 591.4 (M⁺ + 1); 590.13 for C₂₉H₂₆N₄O₆S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.45 (t, J = 5.6 Hz, 1H), 8.06 (d,J = 8.2 Hz, 1H), 8.03-7.95 (m, 3H), 7.93-7.84 (m, 3H), 7.84-7.78 (m,3H), 7.72 (s, 1H), 7.01 (dd, J = 8.9, 2.2 Hz, 2H), 4.66 (d, J = 5.5 Hz,2H), 4.06-4.01 (m, 2H), 3.28-3.14 (m, 2H), 1.91-1.81 (m, 2H), 1.79 (s,3H);  1992

A^(c), 92, 375 45 617.1 (M⁺ + 1); 616.18 C₃₂H₃₂N₄O₅S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.52 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.3Hz, 1H), 7.98 (td, J = 7.5, 1.0 Hz, 2H), 7.93- 7.79 (m, 6H), 7.72 (s,1H), 7.02 (d, J = 8.9 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.08 (t, J =5.9 Hz, 2H), 3.04-2.70 (m, 4H), 2.30-2.14 (m, 2H), 2.12-1.93 (m, 2H),1.75-1.18 (m, 6H);  1993

A, 92, 378 35 619.3 (M⁺ + 1); 618.16 C₃₁H₃₀N₄O₆S₂ ¹H-NMR (DMSO-d₆, 400MHz): δ 11.51 (s, 1H), 9.44 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.3 Hz,1H), 8.01-7.95 (m, 2H), 7.92-7.84 (m, 3H), 7.84-7.77 (m, 3H), 7.72 (s,1H), 7.01 (d, J = 9.0 Hz, 2H), 4.66 (d, J = 5.6 Hz, 2H), 4.06 (t, J =6.4 Hz, 2H), 3.59-3.53 (m, 4H), 2.41 (t, J = 7.2 Hz, 2H), 2.37-2.33 (m,4H), 1.92-1.84 (m, 2H);  1994

A^(c), 92, 383 38 645.0 (M⁺ + 1); 644.14 for C₃₀H₂₇F₃N₄O₅S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (br s, 1H), 9.44 (t, J = 5.6 Hz, 1H), 8.05(d, J = 8.2 Hz, 1H), 7.98 (td, J = 7.5, 0.8 Hz, 2H), 7.93-7.84 (m, 3H),7.84-7.78 (m, 3H), 7.72 (s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 4.66 (d, J =5.5 Hz, 2H), 4.04 (t, J = 6.2 Hz, 2H), 3.18 (q, J = 10.1 Hz, 2H), 2.67(t, J = 7.0 Hz, 2H), 2.37 (s, 3H), 1.91-1.83 (m, 2H);  1998

A^(b), 92, 411 71 637.1 (M⁺ + 1); 636.17 for C₃₁H₃₂N₄O₇S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.34 (br s, 1H), 9.45 (t, J = 5.8 Hz, 1H), 8.05(d, J = 8.3 Hz, 1H), 7.98 (td, J = 7.4, 1.1 Hz, 2H), 7.93- 7.84 (m, 3H),7.84-7.77 (m, 3H), 7.72 (s, 1H), 7.01 (d, J = 8.9 Hz, 2H), 4.66 (d, J =5.5 Hz, 2H), 4.42-4.25 (m, 2H), 4.06 (t, J = 6.4 Hz, 2H), 3.41 (t, J =6.2 Hz, 4H), 2.61 (t, J = 6.8 Hz, 2H), 2.55-2.51 (m, 4H), 1.83 (p, J =6.7 Hz, 2H); 11047

A^(c), 92, 458A 39 467.0 (M⁺ + 1); 466.05 for C₂₀H₁₄N₆O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.56 (t, J = 5.7 Hz, 1H), 8.85 (s,1H), 8.06 (d, J = 8.2 Hz, 1H), 8.03 (s, 1H), 7.98 (dd, J = 7.5, 1.2 Hz,2H), 7.93-7.80 (m, 4H), 7.76 (s, 1H), 4.68 (d, J = 5.6 Hz, 2H); 11048

A^(c), 92, 458B 23 467.0 (M⁺ + 1); 466.05 for C₂₀H₁₄N₆O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.52 (t, J = 5.6 Hz, 1H), 8.22 (s,2H), 8.06 (d, J = 8.2 Hz, 1H), 7.98 (td, J = 7.6, 1.1 Hz, 2H), 7.93-7.79(m, 4H), 7.67 (s, 1H), 4.66 (d, J = 5.6 Hz, 2H); 11053

A^(c), 92, 476 41  603.20 (M⁺ + 1); 602.20 for C₃₂H₃₄N₄O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.50 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06(d, J = 8.1 Hz, 1H), 8.00-7.96 (m, 2H), 7.93-7.74 (m, 7H), 7.29 (d, J =8.1 Hz, 2H), 4.68 (d, J = 5.2 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H),2.46-2.33 (m, 6H), 1.58 (p, J = 7.5 Hz, 2H), 1.44-1.36 (m, 2H), 0.92 (t,J = 7.0 Hz, 6H); 11054

A^(c), 92, 471 23  603.20 (M⁺ + 1); 602.20 for C₃₂H₃₄N₄O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 9.45 (t, J = 5.6 Hz, 1H), 8.04 (d, J = 8.3 Hz,1H), 7.97 (td, J = 7.9, 1.3 Hz, 2H), 7.92-7.75 (m, 7H), 7.29 (d, J = 8.3Hz, 2H), 4.67 (d, J = 5.5 Hz, 2H), 2.61 (t, J = 7.6 Hz, 2H), 2.54-2.44(m, 3H), 1.62 (p, J = 7.7 Hz, 2H), 1.37 (td, J = 15.0, 7.3 Hz, 2H), 1.00(s, 9H); 11055

A^(c), 92, 474 53 615.1 (M⁺ + 1); 614.20 for C₃₃H₃₄N₄O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.50 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06(d, J = 8.2 Hz, 1H), 7.98 (td, J = 7.6, 1.1 Hz, 2H), 7.93- 7.76 (m, 7H),7.29 (d, J = 8.2 Hz, 2H), 4.68 (d, J = 5.6 Hz, 2H), 2.61 (t, J = 7.5 Hz,2H), 2.30-2.19 (m, 6H), 1.57 (p, J = 7.5 Hz, 2H), 1.49-1.31 (m, 8H);11056

A, 92, 468  8 617.1 (M⁺ + 1); 616.18 for C₃₂H₃₂N₄O₅S₂ ¹H NMR (400 MHz,DMSO- d₆): δ 11.52 (s, 1H), 9.46 (t, J = 5.6 Hz, 1H), 8.06 (d, J = 8.2Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.88 (m, 1H), 7.87-7.76 (m, 6H), 7.29(d, J = 8.1 Hz, 2H), 4.68 (d, J = 5.5 Hz, 2H), 3.53 (t, J = 4.4 Hz, 4H),2.62 (t, J = 7.5 Hz, 2H), 2.35-2.22 (m, 6H), 1.65-1.53 (m, 2H),1.49-1.37 (m, 2H); 11057

A, 92, 480 26 589.1 (M⁺ + 1); 588.15 for C₃₀H₂₈N₄O₅S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.52 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.4Hz, 1H), 7.98 (td, J = 1.1, 7.5 Hz, 2H), 7.90 (td, J = 7.5, 1.4 Hz, 1H),7.87- 7.75 (m, 7H), 7.29 (d, J = 8.2 Hz, 2H), 4.68 (d, J = 5.5 Hz, 2H),3.07-3.00 (m, 2H), 2.61 (t, J = 7.6 Hz, 2H), 1.77 (s, 3H), 1.57 (td, J =15.1, 7.6 Hz, 2H), 1.39 (p, J = 7.3 Hz, 2H); 11073

A^(c), 92, 389 12 605.1 (M⁺ + 1); 604.18 for C₃₁H₃₂N₄O₅S₂ ¹H NMR (400MHz, Acetic acid): δ 8.16 (d, J = 8.7 Hz, 1H), 8.11-8.08 (m, 2H),7.93-7.88 (m, 3H), 7.87- 7.79 (m, 4H), 7.03 (d, J = 9.0 Hz, 2H), 4.87(s, 2H), 4.18 (t, J = 5.7 Hz, 2H), 3.46-3.22 (m, 6H), 2.34- 2.23 (m,2H), 1.35-1.28 (m, 6H); 11080

A, 92, 402 18 591.1 (M⁺ + 1); 590.17 for C₃₀H₃₀N₄O₅S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.47 (m, 1H), 9.44 (t, J = 5.7 Hz, 1H), 8.17 (s, 1H), 8.06(d, J = 8.2 Hz, 1H), 7.98 (t, J = 7.6 Hz, 2H), 7.93-7.76 (m, 6H), 7.72(s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.57 (q, J= 5.5 Hz, 1H), 2.38 (t, J = 7.2 Hz, 2H), 2.17 (s, 6H), 1.87-1.66 (m,2H), 1.26 (d, J = 6.0 Hz, 3H); 11091

B^(a), 92, 414 55 605.1 (M⁺ + 1); 604.18 for C₃₁H₃₂N₄O₅S₂ ¹H-NMR (400MHz, DMSO- d₆): δ 11.50 (br s, 1H), 9.44 (t, J = 5.8 Hz, 1H), 8.05 (d, J= 8.3 Hz, 1H), 7.98 (td, J = 7.5, 1.1 Hz, 2H), 7.92-7.84 (m, 3H),7.83-7.76 (m, 3H), 7.72 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.66 (d, J =5.5 Hz, 2H), 4.04 (t, J = 6.3 Hz, 2H), 2.79-2.73 (m, 1H), 2.48-2.41 (m,2H), 2.13 (s, 3H), 1.85- 1.78 (m, 2H), 0.92 (d, J = 6.5 Hz, 6H); 11092

B^(a), 92, 417 37 603.2 (M⁺ + 1); 602.17 for C₃₁H₃₀N₄O₅S₂ ¹H NMR (400MHz, CD₃COOD): δ 8.14 (d, J = 8.5 Hz, 1H), 8.10-8.07 (m, 2H), 7.93-7.86(m, 3H), 7.86-7.78 (m, 4H), 7.02 (d, J = 8.8 Hz, 2H), 4.86 (s, 2H), 4.16(t, J = 5.8 Hz, 2H), 3.57-3.48 (m, 2H), 3.03 (s, 3H), 2.81-2.76 (m, 1H),2.43-2.32 (m, 2H), 1.33-1.22 (m, 2H), 0.94- 0.92 (m, 2H); 11093

A, 92, 482 13 603.1 (M⁺ + 1); 602.20 C₃₂H₃₄N₄O₄S₂ ¹H NMR (500 MHz, DMSO-d₆): δ 11.50 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.05 (d, J = 8.7 Hz,1H), 7.99-7.77 (m, 9H), 7.29 (d, J = 8.1 Hz, 2H), 4.68 (d, J = 5.8 Hz,2H), 2.76-2.68 (m, 1H), 2.65-2.57 (m, 2H), 2.30 (t, J = 7.2 Hz, 2H),2.05 (s, 3H), 1.61-1.54 (m, 2H), 1.41-1.36 (m, 2H), 0.90 (d, J = 7.0 Hz,6H); 11099

A^(c), 92, 448 41 565.6 (M⁺ + 1); 564.16 for C₂₇H₂₈N₆O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.48 (br s, 1H), 9.45 (t, J = 5.7 Hz, 1H), 8.22(s, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.83 (m, 3H),7.80 (dd, J = 8.3, 1.6 Hz, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 4.59 (d, J =5.6 Hz, 2H), 2.48- 2.45 (m, 2H), 2.21 (t, J = 7.2 Hz, 2H), 2.10 (s, 6H),1.55 (p, J = 7.5 Hz, 2H), 1.46- 1.36 (m, 2H); 11100

A, 92, 448A 38 593.1 (M⁺ + 1); 592.19 for C₂₉H₃₂N₆O₄S₂ ¹H NMR (400 MHz,DMSO- d₆): δ 11.56 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.22 (s, 1H),8.05 (d, J = 8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.92-7.77 (m, 4H), 7.68 (s,1H), 7.50 (s, 1H), 4.59 (d, J = 5.6 Hz, 2H), 3.30-3.14 (m, 8H),1.58-1.51 (m, 2H), 1.45-1.36 (m, 2H), 0.93 (t, J = 7.0 Hz, 6H); 11101

A, 92, 419 32 619.1 (M⁺ + 1); 618.20 for C₃₂H₃₄N₄O₅S₂ ¹H NMR (400 MHz,CD₃COOD): δ 8.15 (d, J = 8.9 Hz, 1H), 8.11-8.06 (m, 2H), 7.93-7.88 (m,3H), 7.86-7.77 (m, 4H), 7.03 (d, J = 8.9 Hz, 2H), 4.87 (s, 2H),4.73-4.63 (m, 1H), 3.43-3.22 (m, 6H), 2.26- 2.15 (m, 2H), 1.37 (d, J =6.0 Hz, 3H), 1.35-1.30 (m, 6H); 11102

A^(c), 92, 406 14 631.1 (M⁺ + 1); 630.12 for C₂₉H₂₅F₃N₄O5S₂ ¹H NMR (400MHz, DMSO- d₆): δ 11.52 (s, 1H), 9.45 (t, J = 5.8 Hz, 1H), 8.06 (d, J =8.4 Hz, 1H), 8.00-7.98 (m, 2H), 7.92-7.79 (m, 6H), 7.72 (s, 1H), 7.01(d, J = 8.9 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.07 (t, J = 6.3 Hz, 2H),3.27-3.17 (m, 2H), 2.76 (s, 2H), 1.90-1.83 (m, 2H); 11105

A, 92, 411 10 589.1 (M⁺ + 1) 588.15 for C₃₀H₂₈N₄O₅S₂ ¹H NMR (400 MHz,DMSO- d₆): δ 11.52 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.05 (d, J =8.3 Hz, 1H), 7.99-7.95 (m, 2H), 7.93-7.77 (m, 6H), 7.71 (s, 2H), 7.00(d, J = 8.8 Hz, 2H), 4.65 (d, J = 5.5 Hz, 2H), 4.04-4.01 (m, 2H),3.48-3.35 (m, 4H), 2.78-2.69 (m, 2H), 2.10-2.02 (m, 2H), 1.81-1.71 (m,2H); 11116

A^(c), 92, 461 45 538.0 (M⁺ + 1) 537.08 for C₂₄H₁₉N₅O₆S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.47 (br s, 1H), 9.51 (t, J = 5.6 Hz, 1H), 8.84(s, 1H), 8.21 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.00-7.95 (m, 2H),7.93-7.77 (m, 4H), 7.63 (s, 1H), 4.64 (d, J = 5.5 Hz, 2H), 4.26 (q, J =7.1 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H); 11112

A^(b), 92, 431 17 603.1 (M⁺ + 1) 602.17 for C₃₁H₃₀N₄O₅S₂ ¹H NMR (400MHz, DMSO- d₆): δ 11.52 (s, 1H), 9.46 (t, J = 5.6 Hz, 1H), 8.06 (d, J =8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.77 (m, 6H), 7.72 (s, 1H), 7.00(d, J = 8.9 Hz, 2H), 4.66 (d, J = 5.6 Hz, 2H), 3.90 (br s, 2H),2.97-2.69 (m, 2H), 2.31-1.97 (m, 6H), 0.69-0.30 (m, 4H); 11113

A^(b), 92, 439 61 617.1 (M⁺ + 1) 616.18 for C₃₂H₃₂N₄O₅S₂ ¹H NMR (400MHz, DMSO- d₆): δ 11.52 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.05 (d, J= 8.2 Hz, 1H), 7.99- 7.94 (m, 2H), 7.92-7.83 (m, 3H), 7.83-7.78 (m, 3H),7.71 (s, 1H), 7.04 (d, J = 8.8 Hz, 2H), 4.65 (d, J = 5.6 Hz, 2H), 4.07(br s, 2H), 2.57-2.51 (m, 1H), 2.46-2.29 (m, 2H), 2.27-2.06 (m, 4H),2.02- 1.79 (m, 7H); 11118

A^(c), 92, 451 27 564.1 (M⁺ + 1); 563.09 for C₂₆H₂₁N₅O₆S₂ ¹H NMR (400MHz, DMSO- d₆): δ 11.51 (s, 1H), 9.48 (t, J = 5.7 Hz, 1H), 8.89 (s, 1H),8.31 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.00-7.79 (m, 6H), 7.62 (s, 1H),7.59- 7.57 (m, 1H), 6.56 (d, J = 16.1 Hz, 1H), 4.62 (d, J = 5.4 Hz, 2H),4.19-4.14 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); 11142

A^(b), 92, 422 48 635.1 (M⁺ + 1) 588.15 for C₃₀H₂₈N₄O₅S₂ ¹H NMR (400MHz, DMSO- d₆): δ 11.52 (s, 1H), 9.45 (t, J = 5.8 Hz, 1H), 8.06 (d, J =8.3 Hz, 1H), 8.00-7.96 (m, 2H), 7.92-7.77 (m, 6H), 7.72 (s, 1H), 7.00(d, J = 8.9 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.04 (t, J = 6.3 Hz, 2H),2.70-2.55 (m, 8H), 2.47- 2.45 (m, 2H), 1.89-1.83 (m, 2H);  1901-A

A^(c), 120, 227 57 531.1 (M⁺ + 1); 530.07 for C₂₆H₁₈N₄O₅S₂ 1H-NMR(DMSO-d6, 400 MHz): δ 11.25 (br s, 1H), 9.07 (t, J = 6.0 Hz, 1H), 8.07(d, J = 8.5 Hz, 2H), 8.01-7.82 (m, 7H), 7.66 (s, 1H), 7.51 (s, 1H), 4.70(d, J = 5.6 Hz, 2H), 3.94 (s, 3H);  1768

A, 95 357 12 506.1 (M⁺ + 1); 505.08 for C₂₅H₁₉N₃O₅S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 10.86 (br s, 1H), 10.00 (br s, 1H), 9.17 (br s, 1H),7.98-7.77 (m, 5H), 7.75-7.65 (m, 3H), 7.35 (d, J = 7.2 Hz, 1H), 6.85 (d,J = 7.9 Hz, 2H), 4.60 (br s, 2H), 2.32 (br s, 3H);  1877

A, 95, 227 68 515.1 (M⁺ + 1); 514.08 for C₂₆H₁₈N₄O₄S₂ ¹H-NMR (DMSO-d₆,500 MHz): δ 10.85 (s, 1H), 9.22 (t, J = 5.8 Hz, 1H), 8.08 (d, J = 8.1Hz, 2H), 7.96-7.88 (m, 5H), 7.87-7.82 (m, 2H), 7.80-7.76 (m, 1H), 7.35(d, J = 8.1 Hz, 1H), 4.67 (d, J = 5.8 Hz, 2H), 2.31 (s, 3H); 11046

A^(c), 92, 528 70 480.0 (M⁺ + 1); 479.07 for C₂₂H₁₇N₅O₄S₂ 1H-NMR(DMSO-d6, 400 MHz): δ 11.52 (br s, 1H), 9.43 (t, J = 5.7 Hz, 1H), 8.05(d, J = 8.2 Hz, 1H), 7.97 (td, J = 8.4, 1.7 Hz, 2H), 7.92-7.81 (m, 3H),7.81-7.77 (m, 2H), 7.70 (s, 1H), 6.66 (d, J = 2.3 Hz, 1H), 4.65 (d, J =5.8 Hz, 2H), 3.87 (s, 3H); 11158

A^(C), 92, 524A 26 588.2 (M⁺ + 1); 587.17 for C₃₀H₂₉N₅O₄S₂ ¹H NMR (400MHz, DMSO- d₆): δ 11.52 (br s, 1H), 9.47 (t, J = 5.8 Hz, 1H), 8.06 (d, J= 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.77 (m, 7H), 7.36 (d, J = 8.2Hz, 2H), 4.68 (d, J = 5.6 Hz, 2H), 3.62 (s, 2H), 3.39 (s, 2H), 2.87-2.85(m, 3H), 2.03 (s, 6H); 11182

A^(C), 92, 440 37 585.1 (M⁺ + 1) 584.12 for C₃₀H₂₄N₄O₅S₂ ¹H NMR (400MHz, DMSO- d₆): δ 11.52 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06 (d, J =8.3 Hz, 1H), 8.00-7.96 (m, 2H), 7.93-7.78 (m, 6H), 7.74 (s, 1H), 7.09(d, J = 8.9 Hz, 2H), 4.67 (d, J = 5.6 Hz, 2H), 4.32 (s, 2H), 2.43- 2.40(m, 2H), 2.31-2.21 (m, 2H), 2.17-2.01 (m, 2H); 11074

A^(C), 95, 455 50 480.0 (M⁺ + 1); 497.07 for C₂₂H₁₇N₅O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 10.86 (s, 1H), 9.20 (t, J = 5.8 Hz, 1H), 8.47 (d,J = 2.3 Hz, 1H), 7.95-7.83 (m, 5H), 7.80 (td, J =, 7.6, 1.5 Hz, 1H),7.54 (s, 1H), 7.35 (d, J = 8.1 Hz, 1H), 6.62 (dd, J = 2.5, 1.8 Hz, 1H),4.58 (d, J = 5.6 Hz, 2H), 2.32 (s, 3H); 11077

A^(c), 95, 354 57  491.08 (M⁺ + 1); 490.08 for C₂₄H₁₈N₄O₄S₂ ¹H NMR (400MHz, DMSO- d₆) δ 10.86 (br s, 1H), 9.21 (t, J = 5.3 Hz, 1H), 8.62 (d, J= 4.4 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.99-7.77 (m, 7H), 7.52-7.44(m, 1H), 7.36 (d, J = 8.1 Hz, 1H), 4.67 (d, J = 5.6 Hz, 2H), 2.33 (s,3H); 11041

A, 113, 255 37 496.0 (M⁺ + 1); 495.05 for C₂₁H₁₆F₃N₃O₄S₂ ¹H NMR(DMSO-d₆, 400 MHz): δ 11.37 (s, 1H), 9.31 (br t, J = 5.8 Hz, 1H), 8.06(s, 1H), 8.00-7.94 (m, 2H), 7.92-7.81 (m, 3H), 7.30 (s, 1H), 4.73 (br d,J = 5.6 Hz, 2H), 2.75-2.63 (m, 2H), 1.07 (t, J = 7.5 Hz, 3H); 11042

A^(c), 113 316 19 547.0 (M⁺ + 1); 546.08 for C₂₇H₁₉FN₄O₄S₂ ¹H NMR(DMSO-d₆, 500 MHz): δ 11.15 (br s, 1H), 9.04 (br t, J = 5.8 Hz, 1H),8.15 (t, J = 8.1 Hz, 1H), 7.90 (br d, J = 11.0 Hz, 1H), 7.80-7.72 (m,3H), 7.70-7.59 (m, 4H), 7.07 (s, 1H), 4.51 (br d, J = 5.8 Hz, 2H), 2.52-2.44 (m, 2H), 0.87 (t, J = 7.5 Hz, 3H); 11082

A, 135, 255 32 503.9 (M⁺ + 1); 500.98 for C₁₉H₁₁ClF₃N₃O₄S₂ ¹H NMR (400MHz, DMSO- d₆): δ 11.18 (br s, 1H), 9.40 (t, J = 5.8 Hz, 1H), 8.06 (s,1H), 8.02-7.93 (m, 3H), 7.90 (td, J = 7.5, 1.3 Hz, 1H), 7.84 (dd, J =7.5, 1.7 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 4.75 (d, J = 5.6 Hz, 2H);11083

A, 135, 316 43 553.0 (M⁺ + 1); 552.01 for C₂₅H₁₄ClFN₄O₄S₂ ¹H NMR (400MHz, DMSO- d₆): δ 11.19 (s, 1H), 9.35 (t, J = 5.9 Hz, 1H), 8.37 (t, J =7.9 Hz, 1H), 8.11 (dd, J = 11.2, 1.4 Hz, 1H), 8.03-7.93 (m, 4H), 7.90(td, J = 7.5, 1.4 Hz, 1H), 7.87-7.80 (m, 2H), 7.50 (d, J = 8.2 Hz, 1H),4.74 (d, J = 5.8 Hz, 2H);  1936

A^(a), 143, 255 49 536.0 (M⁺ + 1); 535.01 for C₂₀H₁₁F₆N₃O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.82 (br s, 1H), 9.47 (t, J = 5.5 Hz, 1H), 8.17(s, 1H), 8.09-7.84 (m, 5H), 7.52 (s, 1H), 4.76 (br d, J = 5.3 Hz, 2H); 1734

A, 200, 357  6 442.0 (M⁺ + 1); 441.11 for C₂₅H₁₉N₃O₃S ¹H-NMR (DMSO-d₆,500 MHz): δ 10.52 (s, 1H), 9.91 (s, 1H), 9.09 (t, J = 5.8 Hz, 1H),7.71-7.60 (m, 5H), 7.54 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H),7.42 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz,1H), 6.81 (d, J = 8.7 Hz, 2H), 4.59 (d, J = 5.8 Hz, 2H), 3.94 (s, 2H); 1557

A, 149, 297 48 365.8 (M⁺ + 1) 365.08 for C₁₉H₁₅N₃O₃S ¹H-NMR (DMSO-d₆,400 MHz): δ 10.62 (s, 1H), 9.12 (t, J = 5.9 Hz, 1H), 7.78 (dd, J = 7.7,1.7 Hz, 1H), 7.67 (s, 1H), 7.65-7.58 (m, 2H), 7.49 (s, 1H), 7.41 (d, J =8.4 Hz, 1H), 7.38-7.31 (m, 2H), 4.55 (d, J = 5.7 Hz, 2H), 2.57 (s, 3H); 1558

A, 149, 239 56 379.9 (M⁺ + 1); 379.10 for C₂₀H₁₇N₃O₃S ¹H-NMR (DMSO-d₆,400 MHz): δ 10.62 (s, 1H), 9.12 (t, J = 5.6 Hz, 1H), 7.78 (dd, J = 7.5,1.4 Hz, 1H), 7.69- 7.58 (m, 3H), 7.52 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H),7.39-7.31 (m, 2H), 4.56 (d, J = 5.6 Hz, 2H), 2.90 (q, J = 7.5 Hz, 2H),1.24 (t, J = 7.5 Hz, 3H);  1559

A, 149, 251 41 393.9 (M⁺ + 1); 393.11 for C₂₁H₁₉N₃O₃S ¹H-NMR (DMSO-d₆,400 MHz): δ 10.62 (s, 1H), 9.12 (t, J = 5.7 Hz, 1H), 7.78 (dd, J = 7.8,1.6 Hz, 1H), 7.68 (s, 1H), 7.66-7.59 (m, 2H), 7.53 (s, 1H), 7.42 (d, J =8.4 Hz, 1H), 7.38-7.30 (m, 2H), 4.57 (d, J = 5.7 Hz, 2H), 3.24-3.19 (m,1H), 1.27 (d, J = 6.9 Hz, 6H);  1561

A, 149, 285  8 446.0 (M⁺ + 1); 445.09 for C₂₄H₁₆FN₃O₃S ¹H NMR (DMSO-d₆,500 MHz): δ 10.64 (s, 1H), 9.22 (t, J = 4.8 Hz, 1H), 7.93 (dd, J = 8.0,5.6 Hz, 2H), 7.78 (br s, 2H), 7.70 (s, 1H), 7.63 (d, J = 3.5 Hz, 2H),7.43 (d, J = 8.4 Hz, 1H), 7.38-7.28 (m, 4H), 4.66 (d, J = 5.2 Hz, 2H); 1562

A, 149, 291 36 428.3 (M⁺ + 1); 427.10 for C₂₄H₁₇N₃O₃S ¹H-NMR (DMSO-d₆,400 MHz): δ 10.59 (s, 1H), 9.18 (t, J = 5.7 Hz, 1H), 7.88-7.84 (m, 2H),7.78- 7.73 (m, 2H), 7.68 (s, 1H), 7.63-7.57 (m, 2H), 7.49-7.38 (m, 4H),7.36-7.28 (m, 2H), 4.64 (d, J = 5.6 Hz, 2H);  1611

A, 149, 304 48 436.9 (M⁺ + 1); 436.12 for C₂₂H₂₀N₄O₄S ¹H-NMR (DMSO-d₆,500 MHz): δ 10.62 (s, 1H), 9.02 (t, J = 5.2 Hz, 1H), 7.78 (d, J = 7.2Hz, 1H), 7.66 (s, 1H), 7.65-7.57 (m, 2H), 7.40 (d, J = 8.4 Hz, 1H),7.38-7.30 (m, 2H), 7.06 (s, 1H), 4.43 (d, J = 5.2 Hz, 2H), 3.68- 3.63(m, 4H), 3.31-3.28 (m, 4H);  1617

A, 149, 288 14 455.3 (M⁺ + 1); 454.11 for C₂₂H₂₂N₄O₃S₂ ¹H-NMR (DMSO-d₆,500 MHz): δ 10.63 (s, 1H), 9.14 (t, J = 5.6 Hz, 1H), 7.78 (d, J = 6.9Hz, 1H), 7.70-7.54 (m, 4H), 7.42 (d, J = 8.4 Hz, 1H), 7.39-7.31 (m, 2H),4.54 (d, J = 5.8 Hz, 2H), 3.27 (t, J = 6.9 Hz, 2H), 2.55 (t, J = 6.9 Hz,2H), 2.15 (s, 6H);  1618

A, 149, 357 34 444.0 (M⁺ + 1); 443.09 for C₂₄H₁₇N₃O₄S ¹H-NMR (DMSO-d₆,500 MHz): δ 10.63 (s, 1H), 9.93 (s, 1H), 9.17 (t, J = 5.6 Hz, 1H), 7.78(d, J = 6.7 Hz, 1H), 7.72-7.59 (m, 6H), 7.42 (d, J = 8.4 Hz, 1H),7.38-7.31 (m, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.62 (d, J = 5.5 Hz, 2H); 1619

A, 149, 363 35 458.0 (M⁺ + 1); 457.11 for C₂₅H₁₉N₃O₄S ¹H-NMR (DMSO-d₆,500 MHz): δ 10.63 (s, 1H), 9.19 (t, J = 5.8 Hz, 1H), 7.82 (d, J = 8.7Hz, 2H), 7.78 (dd, J = 7.7, 1.6 Hz, 1H), 7.72- 7.69 (m, 2H), 7.66-7.61(m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.38-7.31 (m, 2H), 7.02 (d, J = 9.0Hz, 2H), 4.64 (d, J = 5.5 Hz, 2H), 3.80 (s, 3H);  1621

A, 149, 360 14 515.1 (M⁺ + 1); 514.17 for C₂₈H₂₆N₄O₄S ¹H-NMR (DMSO-d₆,400 MHz): δ 10.61 (s, 1H), 9.17 (t, J = 5.3 Hz, 1H), 7.81- 7.74 (m, 3H),7.68 (d, J = 6.7 Hz, 2H), 7.61 (d, J = 7.5 Hz, 2H), 7.41 (d, J = 8.4 Hz,1H), 7.36-7.29 (m, 2H), 7.01 (d, J = 8.4 Hz, 2H), 4.62 (d, J = 5.5 Hz,2H), 4.11 (t, J = 5.5 Hz, 2H), 2.75-2.68 (m, 2H), 2.27 (br s, 6H);  1629

A, 149, 255  9 419.9 (M⁺ + 1); 419.06 for C₁₉H₁₂F₃N₃O₃S ¹H-NMR (DMSO-d₆,400 MHz): δ 10.64 (s, 1H), 9.33 (t, J = 5.6 Hz, 1H), 8.05 (s, 1H), 7.78(dd, J = 7.7, 1.6 Hz, 1H), 7.69 (s, 1H), 7.66- 7.60 (m, 2H), 7.43 (d, J= 8.4 Hz, 1H), 7.39-7.31 (m, 2H), 4.72 (d, J = 5.6 Hz, 2H);  1698

A, 149, 367 48 529.1 (M⁺ + 1); 528.18 for C₂₉H₂₈N₄O₄S ¹H NMR (DMSO-d₆,400 MHz): δ 10.63 (s, 1H), 9.19 (t, J = 5.8 Hz, 1H), 7.82-7.76 (m, 3H),7.71-7.69 (m, 2H), 7.66-7.60 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H),7.39-7.30 (m, 2H), 7.00 (d, J = 8.9 Hz, 2H), 4.63 (d, J = 5.7 Hz, 2H),4.04 (t, J = 6.5 Hz, 2H), 2.34 (t, J = 7.1 Hz, 2H), 2.13 (s, 6H),1.89-1.80 (m, 2H);  1769

A^(a), 149, 219 72 380.0 (M⁺ + 1); 379.10 for C₂₀H₁₇N₃O₃S ¹H-NMR(DMSO-d₆, 500 MHz): δ 10.62 (s, 1H), 9.04 (t, J = 5.6 Hz, 1H), 7.78 (dd,J = 7.7, 1.5 Hz, 1H), 7.67- 7.56 (m, 3H), 7.41 (d, J = 8.4 Hz, 1H),7.38-7.30 (m, 2H), 4.47 (d, J = 5.6 Hz, 2H), 2.54-2.50 (m, 3H), 2.30 (s,3H);  1833

A^(b), 149, 319 70 483.1 (M⁺ + 1); 482.51 for C₂₆H₁₈N₄O₄S ¹H-NMR(DMSO-d₆, 500 MHz): δ 10.74-10.46 (m, 2H), 9.20 (br s, 1H), 7.82- 7.58(m, 6H), 7.47-7.29 (m, 4H), 6.88 (d, J = 7.2 Hz, 1H), 4.64 (br s, 2H),3.54 (br s, 2H);  1835-A

A^(C), 149, 326 32 472.1 (M⁺ + 1); 471.13 for C₂₆H₂₁N₃O₄S ¹H NMR (500MHz, DMSO- d₆): δ 10.60 (s, 1H), 9.09 (t, J = 5.5 Hz, 1H), 7.79-7.76 (m,1H), 7.66-7.53 (m, 4H), 7.40 (d, J = 8.4 Hz, 1H), 7.37-7.31 (m, 2H),7.21 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.53 (d, J = 5.5 Hz,2H), 4.16 (s, 2H), 3.71 (s, 3H);  1941

A, 153, 255 55 434.0 (M⁺ + 1); 433.07 for C₂₀H₁₄F₃N₃O₃S ¹H NMR((DMSO-d₆, 400 MHz): δ 10.06 (s, 1H), 9.10 (t, J = 5.8 Hz, 1H), 8.04 (s,1H), 7.72 (dd, J = 7.7, 1.7 Hz, 1H), 7.62-7.57 (m, 1H), 7.40-7.23 (m,3H), 7.14 (d, J = 8.3 Hz, 1H), 4.69 (d, J = 5.8 Hz, 2H), 2.28 (s, 3H); 1913

A, 155, 227 23 487.1 (M⁺ + 1); 486.06 for C₂₅H₁₅ClN₄O₃S ¹H-NMR (DMSO-d₆,400 MHz): δ 10.64 (br s, 1H), 9.19 (br t, J = 5.4 Hz, 1H), 8.09 (br d, J= 8.0 Hz, 2H), 7.96 (br d, J = 8.2 Hz, 2H), 7.91 (s, 1H), 7.78 (br d, J= 7.3 Hz, 1H), 7.65 (br t, J = 7.3 Hz, 1H), 7.60 (s, 1H), 7.44-7.32 (m,2H), 7.23 (s, 1H), 4.68 (br d, J = 5.4 Hz, 2H);  1732

A, 166, 357 21 457.0 (M⁺ + 1); 456.13 for C₂₅H₂₀N₄O₃S ¹H-NMR (DMSO-d₆,400 MHz): δ 10.29 (s, 1H), 9.93 (s, 1H), 9.08 (t, J = 5.6 Hz, 1H),7.72-7.54 (m, 6H), 7.53-7.47 (m, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.20 (d,J = 8.1 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 8.7 Hz, 2H),4.61 (d, J = 5.5 Hz, 2H);  1751

A, 169, 357 14 471.0 (M⁺ + 1); 470.14 for C₂₆H₂₂N₄O₃S ¹H-NMR (DMSO-d₆,400 MHz): δ 10.30 (s, 1H), 9.95 (br s, 1H), 9.07 (t, J = 5.8 Hz, 1H),7.69 (d, J = 8.8 Hz, 2H), 7.65 (s, 1H), 7.63-7.57 (m, 3H), 7.52-7.46 (m,1H), 7.24 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.13-7.08 (m,1H), 6.82 (d, J = 8.8 Hz, 2H), 4.61 (d, J = 5.6 Hz, 2H), 3.78 (br d, J =5.5 Hz, 2H), 1.12 (t, J = 7.0 Hz, 3H); 11043

A^(c), 185 255 15 475.0 (M⁺ + 1); 474.13 for C₂₃H₂₁F₃N₄O₂S ¹H-NMR(DMSO-d₆, 400 MHz): δ 10.29 (s, 1H), 9.22 (t, J = 5.6 Hz, 1H), 8.04 (s,1H), 7.63-7.54 (m, 3H), 7.51-7.44 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H),7.21 (d, J = 8.1 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 4.70 (d, J = 5.5 Hz,2H), 3.54 (d, J = 7.0 Hz, 2H), 1.81-1.69 (m, 1H), 0.89 (dd, J = 5.3, 4.1Hz, 6H); 11044

A^(b), 185, 316 15 526.1 (M⁺ + 1); 525.16 for C₂₉H₂₄FN₅O₂S ¹H NMR (400MHz, DMSO- d₆): δ 10.28 (s, 1H), 9.16 (t, J = 5.3 Hz, 1H), 8.35 (t, J =7.9 Hz, 1H), 8.09 (d, J = 11.3 Hz, 1H), 7.99 (s, 1H), 7.82 (d, J = 7.8Hz, 1H), 7.71-7.70 (m, 1H), 7.64- 7.51 (m, 3H), 7.47 (t, J = 7.0 Hz,1H), 7.33-7.18 (m, 2H), 7.09 (t, J = 7.4 Hz, 1H), 4.70 (br d, J = 5.2Hz, 2H), 3.54 (d, J = 5.5 Hz, 2H), 1.84- 1.69 (m, 1H), 0.89 (s, 6H); 1920

A, 190, 255 47 459.1 (M⁺ + 1); 458.10 C₂₂H₁₇F₃N₄O₂S ¹H NMR (400 MHz,DMSO- d₆): δ 10.33 (s, 1H), 9.23 (br t, J = 5.6 Hz, 1H), 8.04 (s, 1H),7.63-7.55 (m, 3H), 7.51-7.43 (m, 1H), 7.29-7.18 (m, 2H), 7.11 (t, J =7.6 Hz, 1H), 5.78-5.66 (m, 1H), 5.33 (dd, J = 17.4, 1.2 Hz, 1H),5.16-5.10 (m, 1H), 4.70 (d, J = 5.4 Hz, 2H), 4.45 (d, J = 5.3 Hz, 2H); 1546

A, 211, 217  48% 364.0 (M⁺ + 1); 363.10 for C₂₀H₁₇N₃O₂S ¹H-NMR (DMSO-d₆,400 MHz): δ 10.64-10.51 (m, 1H), 9.10 (t, J = 4.4 Hz, 1H), 8.95 (d, J =2.7 Hz, 1H), 7.82-7.75 (m, 1.5 H), 7.69- 7.57 (m, 2H), 7.55-7.46 (m, 1.5H), 7.43-7.29 (m, 3H), 4.64 (d, J = 2.8 Hz, 2H), 4.27-4.09 (m, 1H),1.77, 1.44 (d, J = 7.1 Hz, 3H);  1548

A, 211 297  48% 377.9 (M⁺ + 1); 377.12 for C₂₁H₁₉N₃O₂S ¹H-NMR (DMSO-d₆,400 MHz): δ 10.69-10.44 (m, 1H), 9.05 (t, J = 4.5 Hz, 1H), 7.77 (d, J =7.1 Hz, 0.5H), 7.65 (d, J = 6.6 Hz, 0.5H), 7.62-7.57 (m, 1.5 H),7.54-7.46 (m, 2.5H), 7.43- 7.29 (m, 3H), 4.58-4.49 (m, 2H), 4.28-4.07(m, 1H), 2.56 (d, J = 2.6 Hz, 3H), 1.77, 1.43 (d, J = 7.3 Hz, 3H);  1697

A, 149, 312 68 471.0 (M⁺ + 1); 470.14 for C₂₆H₂₂N₄O₃S 1H-NMR (DMSO-d6,400 MHz): δ 10.77 (s, 1H), 9.29 (t, J = 5.6 Hz, 1H), 7.95-7.90 (m, 1H),7.85-7.74 (m, 6H), 7.56 (d, J = 8.4 Hz, 1H), 7.52-7.44 (m, 2H), 6.88 (d,J = 9.0 Hz, 2H), 4.74 (d, J = 5.8 Hz, 2H), 3.10 (s, 6H);  1754

A, 211, 357 37 456.0 (M⁺ + 1); 455.13 for C₂₆H₂₁N₃O₃S ¹H-NMR (DMSO-d₆,400 MHz) (rotamers): δ 10.74- 10.45 (m, 1H), 9.93 (br s, 1H), 9.11 (t, J= 4.8 Hz, 1H), 7.80-7.46 (m, 7H), 7.43-7.28 (m, 3H), 6.83 (dd, J = 9.2,2.5 Hz, 2H), 4.66-4.57 (m, 2H), 4.27-4.09 (m, 1H), 1.77, 1.44 (d, J =7.3 Hz, 3H);  1592

A, 216, 297 42 377.8 (M⁺ + 1); 377.08 for C₂₀H₁₅N₃O₃S ¹H-NMR (DMSO-d₆,500 MHz): 11.19 (s, 1H), 9.28 (t, J = 5.8 Hz, 1H), 8.20-8.14 (m, 1H),7.87-7.76 (m, 5H), 7.60 (dd, J = 8.2, 1.3 Hz, 1H), 7.50 (s, 1H), 4.57(d, J = 5.8 Hz, 2H), 2.57 (s, 3H);  1594

A, 216, 291 30 440.5 (M⁺ + 1); 439.10 for C₂₅H₁₇N₃O₃S ¹H NMR (400 MHz,DMSO- d₆): δ 11.21 (br s, 1H), 9.40 (t, J = 5.6 Hz, 1H), 8.21-8.16 (m,1H), 7.93-7.79 (m, 8H), 7.65 (dd, J = 8.3, 1.5 Hz, 1H), 7.52-7.44 (m,3H), 4.70 (d, J = 5.5 Hz, 2H);  1916

Ac, 172, 255 58 461.1 (M⁺ + 1); 460.12 C₂₂H₁₉F₃N₄O₂S 1H-NMR (DMSO-d6,400 MHz): δ 10.29 (s, 1H), 9.22 (t, J = 5.8 Hz, 1H), 8.04 (s, 1H),7.62-7.56 (m, 3H), 7.51-7.45 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.21 (d,J = 7.8 Hz, 1H), 7.13-7.08 (m, 1H), 4.70 (d, J = 5.5 Hz, 2H), 3.72 (t, J= 5.7 Hz, 2H), 1.57-1.44 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H);  1917

A^(c), 172, 227 30 494.1 (M⁺ + 1); 493.16 C₂₈H₂₃N₅O₂S ¹H NMR (400 MHz,DMSO- d₆): δ 10.29 (s, 1H), 9.15 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.4Hz, 2H), 7.96-7.88 (m, 3H), 7.64-7.56 (m, 3H), 7.51-7.44 (m, 1H), 7.29-7.18 (m, 2H), 7.10 (t, J = 7.4 Hz, 1H), 4.68 (d, J = 5.8 Hz, 2H),3.77-3.69 (m, 2H), 1.55-1.47 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H);  1921

A^(c), 190, 227 46 492.1 (M⁺ + 1); 491.14 C₂₈H₂₁N₅O₂S ¹H NMR (400 MHz,DMSO- d₆): δ 10.34 (s, 1H), 9.16 (t, J = 5.5 Hz, 1H), 8.06 (d, J = 8.3Hz, 2H), 7.95-7.88 (m, 3H), 7.64-7.56 (m, 3H), 7.48 (t, J = 7.1 Hz, 1H),7.29-7.17 (m, 2H), 7.10 (t, J = 7.5 Hz, 1H), 5.79-5.66 (m, 1H), 5.33 (d,J = 17.3 Hz, 1H), 5.13 (d, J = 10.2 Hz, 1H), 4.68 (d, J = 5.3 Hz, 2H),4.44 (d, J = 4.9 Hz, 2H);  1922

A, 176, 255 475.1 (M⁺ + 1); 474.13 for C₂₃H₂₁F₃N₄O₂S ¹H NMR (400 MHz,DMSO- d₆): δ 10.28 (s, 1H), 9.22 (t, J = 5.8 Hz, 1H), 8.04 (d, J = 0.9Hz, 1H), 7.62-7.56 (m, 3H), 7.50-7.47 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H),7.21 (d, J = 7.8 Hz, 1H), 7.13-7.07 (m, 1H), 4.70 (d, J = 5.6 Hz, 2H),3.79-3.72 (m, 2H), 1.53-1.43 (m, 2H), 1.38-1.28 (m, 2H), 0.82 (t, J =7.3 Hz, 3H);  1934

A, 126, 255 20 501.9 (M⁺ + 1); 500.98 for C₁₉H₁₁ClF₃N₃O₄S₂ 1H-NMR(DMSO-d6, 400 MHz): δ 11.50 (br s, 1H), 9.43 (t, J = 5.8 Hz, 1H), 8.06(s, 1H), 8.02-7.96 (m, 3H), 7.95-7.85 (m, 2H), 7.43 (s, 1H), 4.76 (d, J= 5.8 Hz, 2H);  1935

A, 126, 227 35 535.1 (M⁺ + 1); 534.02 for C₂₅H₁₅ClN₄O₄S₂ 1H NMR (400MHz, DMSO- d6): δ 11.52 (s, 1H), 9.36 (t, J = 5.8 Hz, 1H), 8.10 (d, J =8.4 Hz, 2H), 8.02-7.94 (m, 5H), 7.93-7.85 (m, 3H), 7.43 (s, 1H), 4.72(d, J = 5.8 Hz, 2H);  1942

A^(c), 153, 227 59 467.0 (M⁺ + 1); 466.11 for C₂₆H₁₈N₄O₃S 1H-NMR(DMSO-d6, 400 MHz): δ 10.05 (s, 1H), 9.04 (t, J = 5.9 Hz, 1H), 8.09 (d,J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 7.89 (s, 1H), 7.72 (dd, J =7.7, 1.6 Hz, 1H), 7.64-7.55 (m, 1H), 7.38-7.29 (m, 2H), 7.26 (d, J = 8.3Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H) 4.65 (d, J = 5.8 Hz, 2H), 2.29 (s,3H);  1971

A, 95, 316 64 533.0 (M⁺ + 1); 532 for C₂₆H₁₇FN₄O₄S₂ ¹H NMR (400 MHz,DMSO- d₆): δ 10.29 (s, 1H), 9.15 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.4Hz, 2H), 7.96-7.88 (m, 3H), 7.64-7.56 (m, 3H), 7.51-7.44 (m, 1H), 7.29-7.18 (m, 2H), 7.10 (t, J = 7.4 Hz, 1H), 4.68 (d, J = 5.8 Hz, 2H),3.77-3.69 (m, 2H), 1.55-1.47 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H);  1974

A, 166, 227 23 466.1 (M⁺ + 1); 465.13 for C₂₆H₁₉N₅O₂S 1H-NMR (DMSO-d6,400 MHz): δ 10.30 (s, 1H), 9.17 (t, J = 5.5 Hz, 1H), 8.07 (d, J = 8.3Hz, 2H), 7.92 (t, J = 8.5 Hz, 3H), 7.66-7.57 (m, 3H), 7.54-7.47 (m, 1H),7.23 (t, J = 8.8 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H), 4.68 (d, J = 5.6 Hz,2H), 3.31 (s, 3H);  1975

A, 169, 227 24 480.1 (M⁺ + 1); 479.14 for C₂₇H₂₁N₅O₂S 1H-NMR (DMSO-d6,400 MHz): δ 10.31 (s, 1H), 9.17 (t, J = 5.5 Hz, 1H), 8.06 (d, J = 8.3Hz, 2H), 7.95-7.87 (m, 3H), 7.66-7.56 (m, 3H), 7.49 (t, J = 7.0 Hz, 1H),7.27-7.17 (m, 2H), 7.10 (t, J = 7.5 Hz, 1H), 4.68 (d, J = 5.4 Hz, 2H),3.80-3.77 (m, 2H), 1.12 (t, J = 6.9 Hz, 3H); 11001

A, 92, 394 40 591.1 (M⁺ + 1); 590.17 for C₃₀H₃₀N₄O₅S₂ ¹H NMR (400 MHz,DMSO- d₆): δ 11.47 (br s, 1H), 9.44 (t, J = 5.7 Hz, 1H), 8.05 (d, J =8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.77 (m, 6H), 7.72 (s, 1H), 7.01(d, J = 8.9 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 4.03 (t, J = 6.5 Hz, 2H),2.24 (t, J = 7.2 Hz, 2H), 2.12 (s, 6H), 1.77-1.68 (m, 2H), 1.58-1.49 (m,2H); 11117-A

A^(c), 92, 519 26 508.0 (M⁺ + 1); 507.10 for C₂₄H₂₁N₅O₄S₂ ¹H NMR (400MHz, DMSO- d₆): δ 11.52 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.21 (s, 1H),8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93- 7.78 (m, 4H), 7.73(s, 1H), 7.50 (s, 1H), 4.60 (d, J = 5.5 Hz, 2H), 2.88-2.81 (m, 1H), 1.20(d, J = 6.9 Hz, 6H); 11078

A^(c), 194, 255 19 463.1 (M⁺ + 1); 462.10 for C₂₁H₁₇F₃N₄O₃S ¹H NMR (400MHz, DMSO- d₆): δ 10.27 (s, 1H), 9.22 (t, J = 5.8 Hz, 1H), 8.04 (s, 1H),7.63-7.56 (m, 3H), 7.52-7.46 (m, 1H), 7.31- 7.21 (m, 2H), 7.11 (t, J =7.5 Hz, 1H), 4.70 (d, J = 5.6 Hz, 2H), 4.66 (t, J = 5.4 Hz, 1H),3.86-3.82 (m, 2H), 3.51 (q, J = 6.1 Hz, 2H); 11079

A^(c), 194, 316 26 514.1 (M⁺ + 1); 513.13 for C27H20FN5O3S ¹H NMR (400MHz, DMSO- d₆): δ 10.27 (s, 1H), 9.17 (t, J = 5.9 Hz, 1H), 8.35 (t, J =7.9 Hz, 1H), 8.09 (dd, J = 11.1, 1.4 Hz, 1H), 7.99 (d, J = 2.3 Hz, 1H),7.82 (dd, J = 8.2, 1.5 Hz, 1H), 7.62- 7.56 (m, 3H), 7.52-7.46 (m, 1H),7.28 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.10 (t, J = 7.2 Hz,1H), 4.71 (d, J = 5.6 Hz, 2H), 4.66 (t, J = 5.4 Hz, 1H), 3.86-3.82 (m,2H), 3.51 (q, J = 6.2 Hz, 2H); 11094

A, 92, 484 38 601.1 (M⁺ + 1); 600.19 for C₃₂H₃₂N₄O₄S₂ ¹H NMR (400 MHz,DMSO- d₆): δ 11.51 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 8.3Hz, 1H), 7.98 (td, J = 7.4, 1.4 Hz, 2H), 7.90 (td, J = 1.5, 7.5 Hz, 1H),7.87-7.75 (m, 6H), 7.28 (d, J = 8.3 Hz, 2H), 4.68 (d, J = 5.6 Hz, 2H),2.60 (t, J = 7.5 Hz, 2H), 2.47-2.47 (m, 2H), 2.19 (br s, 3H), 1.55 (td,J = 7.3, 14.7 Hz, 3H), 1.48-1.39 (m, 2H), 0.38 (br d, J = 4.0 Hz, 2H),0.24 (br s, 2H); C20-01

B, 20, 367 46  559.20 (M⁺ + 1) 558.18 for C₃₀H₃₀N₄O₃S₂ ¹H NMR (400 MHz,DMSO- d₆): δ 10.25 (s, 1H), 9.03 (t, J = 5.6 Hz, 1H), 7.81 (d, J = 8.8Hz, 2H), 7.68-7.64 (m, 2H), 7.53-7.43 (m, 4H), 7.10-7.01 (m, 3H), 4.59(d, J = 5.6 Hz, 2H), 4.06 (t, J = 6.4 Hz, 2H), 2.45 (t, J = 6.4 Hz, 2H),2.29 (s, 3H), 2.25 (s, 6H), 1.88 (t, J = 6.4 Hz, 2H) C20-02

B, 20, 455 64  448.05 (M⁺ + 1) 447.08 for C₂₂H₁₇N₅O₂S₂ ¹H NMR (400 MHz,DMSO- d₆): δ 10.26 (s, 1H), 9.07 (t, J = 5.6 Hz, 1H), 8.47 (d, J = 1.6Hz, 1H), 7.84 (s, 1H), 7.68-7.64 (m, 1H), 7.52-7.43 (m, 5H), 7.08 (d, J= 8.4 Hz, 1H), 6.62 (s, 1H), 4.56 (d, J = 5.6 Hz, 2H), 2.29 (s, 3H)C38-01

B, 95, 367 21  591.15 (M⁺ + 1) 590.17 for C₃₀H₃₀N₄O₅S₂ ¹H NMR (400 MHz,DMSO- d₆): δ 10.87 (s, 1H), 9.18 (t, 1H), 7.94-7.77 (m, 7H), 7.71 (s,1H), 7.35 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 2H), 4.62 (d, J =5.6 Hz, 2H), 4.08 (t, J = 6.0 Hz, 2H), 2.72-2.70 (m, 2H), 2.43 (s, 6H),2.32 (s, 3H), 1.97-1.94 (m, 2H) C38-02

B, 95, 455 23  480.10 (M⁺ + 1) 479.07 for C₂₂H₁₇N₅O₄S₂ ¹H NMR (400 MHz,DMSO- d₆): δ 10.87 (s, 1H), 9.21 (t, J = 5.6 Hz, 1H), 8.47 (s, 1H),7.94-7.77 (m, 5H), 7.54 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.62 (s, 1H),4.58 (d, J = 5.6 Hz, 2H), 2.32 (s, 3H) C44-01

B, 153, 367 20 543   (M⁺ + 1) 542.20 for C₃₀H₃₀N₄O₄S ¹H NMR (400 MHz,DMSO- d₆): δ 10.05 (s, 1H), 8.97 (t, J = 5.9 Hz, 1H), 7.85-7.76 (m, 2H),7.74-7.65 (m, 2H), 7.58 (td, J = 7.7, 1.8 Hz, 1H), 7.37-7.21 (m, 2H),7.10 (d, J = 8.3 Hz, 1H), 7.05-6.97 (m, 2H), 4.58 (d, J = 5.8 Hz, 2H),4.04 (t, J = 6.4 Hz, 2H), 2.40 (t, J = 7.2 Hz, 2H), 2.27 (s, 3H), 2.18(s, 6H), 1.86 (p, J = 6.6 Hz, 2H) C51-01

B, 135, 367 27 611   (M⁺ + 1) 610.11 for C₂₉H₂₇ClN₄O₅S₂ ¹H NMR (400 MHz,DMSO- d₆) δ 9.26 (t, J = 5.8 Hz, 1H), 8.00-7.76 (m, 7H), 7.71 (s, 1H),7.41 (d, J = 8.0 Hz, 1H), 7.06-6.98 (m, 2H), 4.64 (d, J = 5.6 Hz, 2H),4.05 (t, J = 6.4 Hz, 2H), 2.37 (t, J = 6.8 Hz, 2H), 2.15 (s, 6H), 1.89-1.83 (m, 2H) C51-02

B, 135, 455 20 500   (M⁺ + 1) 499.02 for C₂₁H₁₄ClN₅O₄S₂ ¹H NMR (400 MHz,DMSO- d₆): δ 11.21 (s, 1H), 9.30 (t, J = 5.8 Hz, 1H), 8.47 (d, J = 2.6Hz, 1H), 8.03-7.79 (m, 6H), 7.57-7.45 (m, 2H), 6.62 (s, 1H), 4.60 (d, J= 5.8 Hz, 2H) A^(a): DIPEA (2 equiv); A^(b): EDCI (2 equiv), HOBt (2equiv), DIPEA (5 equiv); A^(c): DIPEA (5 equiv); A^(d): Columnpurification done in neutral alumina (Eluent: 1:1:50,MeOH:NH₄OH:CH₂Cl₂); B^(a): HATU (1.5 equiv), Amine (1.1 (equiv), DIPEA(3 equiv)

Synthesis of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(535): A Common Intermediate

Synthesis of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f][1, 4] thiazepine-8-carboxamide 5, 5-dioxide(535)

To a stirring solution of compound 92 (600 mg, 1.65 mmol) in DMF (15 mL)under inert atmosphere were added compound 223 (362 mg, 1.98 mmol),EDCI.HCl (597 mg, 3.30 mmol), HOBt (445 mg, 3.30 mmol) anddiisopropylethylamine (1.5 mL, 8.25 mmol) at 0° C.; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with water (100 mL) andextracted with EtOAc (2×100 mL). The combined organic extracts weredried over sodium sulphate, filtered and concentrated in vacuo to obtainthe crude. The crude was triturated with EtOAc (10 mL), diethyl ether(10 mL), n-hexane (20 mL) and dried in vacuo to afford compound 535 (700mg, 82%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4);¹H-NMR (DMSO-d₆ 400 MHz): δ 11.51 (br s, 1H), 9.48 (t, J=5.5 Hz, 1H),8.06 (d, J=8.3 Hz, 1H), 7.98 (td, J=7.4, 1.1 Hz, 2H), 7.93-7.83 (m, 3H),7.79 (dd, J=8.3, 1.5 Hz, 1H), 7.61 (s, 1H), 4.59 (d, J=5.5 Hz, 2H).

Synthesis of N-((2-chlorothiazol-5-yl) methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(536): A Common Intermediate

Synthesis of N-((2-chlorothiazol-5-yl) methyl)-9-methyl-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(536)

To a stirring solution of compound 95 (1.5 g, 4.73 mmol) in DMF (15 mL)under inert atmosphere were added EDCI.HCl (1.36 g, 7.09 mmol), HOBt(960 mg, 7.09 mmol), (2-chlorothiazol-5-yl) methanamine hydrochloride223 (963 mg, 7.09 mmol) and diisopropylethylamine (4.1 mL, 23.65 mmol)at 0° C.; warmed to RT and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture waspoured into ice-cold water (100 mL) and extracted with EtOAc (2×60 mL)and dried in vacuo to afford compound 536 (1.2 g, 57%) as white solid.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ 10.86 (s,1H), 9.21 (t, J=5.8 Hz, 1H), 7.95-7.90 (m, 2H), 7.89-7.84 (m, 2H),7.82-7.77 (m, 1H), 7.60 (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 4.56 (d, J=5.6Hz, 2H), 2.31 (s, 3H); LC-MS: 99.42%; 448.0 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.08 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-((2-(4-bromophenyl) thiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(538): A Common Intermediate

Synthesis of (2-(4-bromophenyl) thiazol-5-yl) methanamine hydrochloride(537)

To a stirring solution of compound 463 (700 mg, 1.89 mmol) in CH₂Cl₂ mL)was added 4 N HCl in 1, 4-dioxane (3 mL) under inert atmosphere at 0°C.; warmed to RT and stirred for 3-4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was triturated with diethyl ether (2×5 mL) and dried invacuo to afford compound 537 (680 mg, HCl salt) as an off-white solid.TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 8.64 (brs, 3H), 8.00 (s, 1H), 7.88 (d, J=8.5 Hz, 2H), 7.72 (d, J=8.7 Hz, 2H),4.34 (q, J=5.6 Hz, 2H);

Synthesis of N-((2-(4-bromophenyl) thiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(538)

To a stirring solution of 92 (400 mg, 1.32 mmol) in DMF (15 mL) underinert atmosphere were added HOBt (268 mg, 1.98 mmol), EDCI.HCl (380 mg,1.98 mmol), ((2-(4-bromophenyl) thiazol-5-yl) methanamine 537 (402 mg,1.32 mmol) and diisopropylethylamine (1.2 mL, 6.60 mmol) at 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (50 mL) and extracted with EtOAc (2×50 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude, which was triturated with EtOAc (20 mL) anddried in vacuo to afford compound 538 (500 mg, 68%) as an off-whitesolid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H NMR (DMSO-d₆, 400 MHz): δ11.12 (br s, 1H), 9.48 (t, J=5.8 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.98(td, J=7.4, 1.1 Hz, 2H), 7.93-7.79 (m, 7H), 7.67 (d, J=8.7 Hz, 2H), 4.69(d, J=5.6 Hz, 2H); LC-MS: 97.62%; 555.9 (M+2)⁺; (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.57 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] oxazepine-8-carboxamide (539): A CommonIntermediate

Synthesis of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] oxazepine-8-carboxamide (539)

To a stirring solution of compound 149 (500 mg, 1.96 mmol) in DMF (10mL) under inert atmosphere were added compound 223 (398 mg, 2.15 mmol),EDCI.HCl (561 mg, 2.94 mmol), HOBt (397 mg, 2.94 mmol) anddiisopropylethylamine (1.75 mL, 9.80 mmol) at 0° C.; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with ice cold-water (50mL), extracted with EtOAc (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 8% MeOH/CH₂Cl₂ to afford compound 539 (390 mg, 52%)as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR(DMSO-d₆ 500 MHz): δ 10.63 (s, 1H), 9.23 (t, J=5.6 Hz, 1H), 7.78 (dd,J=7.7, 1.6 Hz, 1H), 7.68 (s, 1H), 7.65-7.58 (m, 3H), 7.43 (d, J=8.4 Hz,1H), 7.39-7.31 (m, 2H), 4.56 (d, J=5.8 Hz, 2H).

The common intermediates 535, 536, 538 & 539 were converted to finalproducts through the displacement reaction using amines or were coupledwith either commercially available coupling reagents or preparedcoupling reagents.

Commercially Available Amines for Displacement Reaction:

Preparation of Amines for Displacement Reaction:

Synthesis of (3S,6S)-azepane-3, 6-diol (550)

Synthesis of (3S,6S)-1-benzylazepane-3, 6-diol (549)

To a stirring solution of 1, 2-di(oxiran-2-yl) ethane 547 (1.5 g, 13.14mmol) in EtOH (40 mL) under argon atmosphere was added benzyl amine 548(1.53 mL, 14.46 mmol) at RT and heated to reflux for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the volatileswere concentrated in vacuo to obtain the crude. The crude was purifiedpreparative HPLC purification to afford compound 549 (600 mg, crude) ascolorless liquid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H NMR (DMSO-d₆,400 MHz): δ 7.36-7.28 (m, 4H), 7.26-7.19 (m, 1H), 4.38 (d, J=4.8 Hz,2H), 3.72-3.50 (m, 4H), 2.73-2.69 (m, 2H), 2.40-2.37 (m, 2H), 1.88-1.67(m, 2H), 1.48-1.27 (m, 2H); LC-MS: 89.13%; 222.2 (M⁺+1); (Column;X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 7.28 min. 2.5 mM(NH₄)₂CO₃:ACN, 1.0 mL/min).

Synthesis of (3S, 6S)-azepane-3,6-diol (550)

To a stirring solution of compound 549 (500 mg, 0.22 mmol) in MeOH (25mL) under inert atmosphere was added 10% Pd/C (50 mg, 50% wet) at RT andstirred under hydrogen atmosphere (balloon pressure) for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite, and eluted with MeOH (10mL). The filtrate was concentrated in vacuo to afford compound 550 (250mg, 84%) as pale yellow solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f). 0.1); ¹H-NMR(DMSO-d₆, 400 MHz): δ 4.55-4.22 (m, 2H), 3.59-3.51 (m, 2H), 2.87-2.83(m, 2H), 2.48-2.43 (m, 2H), 1.80-1.71 (m, 2H), 1.40-1.27 (m, 2H); Mass(Agilent 6310 Ion trap): 132.3 (M⁺+1);

Synthesis of 3, 3-dimethylpyrrolidine (554)

Synthesis of 1-benzyl-3, 3-dimethylpyrrolidine-2, 5-dione (552)

To a stirring solution of 2, 2-dimethylsuccinic acid 551 (5 g, 34.21mmol) in xylene (50 mL) under inert atmosphere was added benzyl amine548 (4.03 g, 37.63 mmol) at RT; heated to 120° C. and stirred for 3 h.The reaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The residue was diluted with EtOAc (100mL), washed with 5% sodium bicarbonate solution. The organic extract wasdried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude compound was precipitated in isopropanol (100 mL)at −40° C. The solvent was decanted and the obtained solid was and driedin vacuo to afford compound 552 (3 g, 40%) as white solid. TLC: 20%EtOAc/hexanes (R_(f). 0.8); ¹H-NMR (DMSO-d₆, 400 MHz): δ 7.35-7.20 (m,5H), 4.55 (s, 2H), 2.65 (s, 2H), 1.22 (s, 6H); LC-MS: 99.27%; 217.9(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.27 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 1-benzyl-3, 3-dimethylpyrrolidine (553)

To a stirring solution of compound 552 (3.0 g, 13.82 mmol) in THF (50mL) under argon atmosphere was added lithium aluminium hydride (1.57 g,41.47 mmol) portion wise for 10 min at 0° C.; warmed to RT and stirredfor 16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was cooled to 0° C., quenched withsaturated sodium sulfate and stirred for 20 min, filtered throughcelite. The celite pad was eluted with EtOAc (30 mL). The filtrate wasdried over sodium sulfate, filtered and concentrated in vacuo to affordcompound 553 (2.2 g, 85%) as colorless thick syrup. ¹H NMR (DMSO-d₆, 400MHz): δ 7.32-7.27 (m, 4H), 7.25-7.19 (m, 1H), 3.52 (s, 2H), 2.56-2.47(m, 2H), 2.21 (s, 2H), 1.51 (t, J=7.1 Hz, 2H), 1.03 (s, 6H); LC-MS:92.64%; 190.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.47 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 3, 3-dimethylpyrrolidine (554)

To a stirring solution of compound 553 (1.5 g, 7.98 mmol) in MeOH (20mL) under inert atmosphere was added 10% Pd/C (500 mg) at RT and stirredunder hydrogen atmosphere (70 psi) at RT; heated to 75° C. for 24 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite and eluted with 20%MeOH/CH₂Cl₂ (2×80 mL). The filtrate was concentrated in vacuo to affordcompound 554 (500 mg, 64%) as colorless thick syrup. TLC: 5% MeOH/CH₂Cl₂(R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 3.03 (t, J=7.4 Hz, 2H), 2.65(s, 2H), 1.55 (t, J=7.3 Hz, 2H), 1.45-1.40 (m, 1H), 1.04 (s, 6H).

Commercially Available Cross Coupling Reagents Used for PreparingCompounds:

Preparation of Cross Coupling Reagents Used in the Preparation ofCompounds:

Synthesis of 2, 6-difluoro-4-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenol (586)

Synthesis of 2, 6-difluoro-4-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenol (586)

To a stirring solution of 4-bromo-2, 6-difluorophenol 585 (1 g, 4.80mmol) in 1, 4-dioxane (25 mL) under inert atmosphere were added bispinacolato diboron (1.83 g, 7.21 mmol), potassium carbonate (1.98 g,14.40 mmol) and purged under argon atmosphere for 10 min. To this wasadded Pd(dppf)Cl₂ (350 mg, 0.48 mmol) and the reaction mixture washeated to 100° C. for 4 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was filtered throughcelite, eluted with CH₂Cl₂ (75 mL). The filtrate was concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 2-5% EtOAc/hexanes to compound 586 (620 mg,50%) TLC: 10% EtOAc/hexanes (R_(f): 0.5).

Synthesis of (6-(dimethylamino) pyridin-3-yl) boronic acid hydrochloride(588)

Synthesis of (6-(dimethylamino) pyridin-3-yl) boronic acid hydrochloride(588)

To a stirring solution of 5-bromo-N, N-dimethylpyridin-2-amine 587 (250mg, 1.24 mmol) in dry THF (10 mL) under inert atmosphere was addedn-butyl lithium (1.6 M solution in hexane, 0.93 mL, 1.49 mmol) drop wisefor 5 min at −78° C. and stirred for 30 min. To this was addedtriisopropyl borate (0.43 mL, 1.86 mmol) in dry THF (4 mL) at −78° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was quenched with2 N aqueous HCl (10 mL). The volatiles were removed in vacuo to obtainthe crude, which washed with diethylether (2×10 mL) to afford compound588 (250 mg, crude) as an off-white thick syrup. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.1); LC-MS: 74.20%; 166.7 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 0.48 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (6-((tert-butoxycarbonyl) amino) pyridin-3-yl) boronic acid(591)

Synthesis of tert-butyl (5-bromopyridin-2-yl) carbamate (590)

To a stirring solution of 5-bromopyridin-2-amine 589 (1 g, 5.78 mmol) inTHF (20 mL) under argon atmosphere were added triethyl amine (2.5 mL,17.32 mmol), Boc-anhydride (1.51 g, 6.92 mmol) and DMAP (70 mg, 0.57mmol) at 0° C.; heated to reflux and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo to obtain the crude. The crude was purified throughsilica gel flash column chromatography using 2-5% EtOAc/hexanes toafford compound 590 (900 mg, 57%) as white solid. TLC: 5% EtOAc/hexanes(R_(f): 0.8); ¹H-NMR (CDCl₃, 400 MHz): δ 8.32 (d, J=2.4 Hz, 1H), 8.02(br s, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.75 (dd, J=8.9, 2.4 Hz, 1H), 1.54(s, 9H).

Synthesis of (6-((tert-butoxycarbonyl) amino) pyridin-3-yl) boronic acid(591)

To a stirring solution of compound 590 (250 mg, 0.91 mmol) and in dryTHF (10 mL) under inert atmosphere was added n-butyl lithium (1.6 Msolution in hexane, 1.72 mL, 2.74 mmol) drop wise for 10 min at −78° C.and stirred for 1 h. To this was added triisopropyl borate (0.31 mL,1.37 mmol) at −78° C. and stirred for 1 h; warmed to RT and stirred for16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was quenched with water (5 mL) and thevolatiles were removed in vacuo to obtain the crude. The pH of the crudewas adjusted to ˜5-6 with 1 N HCl. The volatiles were removed in vacuoto afford compound 591 (300 mg, crude) as white semi solid. TLC: 5%EtOAc/hexanes (R_(f): 0.1); LC-MS: 30.85%; 239.0 (M⁺+1); (column; XSelect CSH C-18, (50×3.0 mm, 2.5 μm); RT 2.54 min. 2.5 mM Aq. NH₄OOCH+5%ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 2-methoxy-5-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) pyrimidine (594)

Synthesis of 5-bromo-2-methoxypyrimidine (593)

Sodium metal (230 mg, 1.03 mmol) was dissolved in MeOH (25 mL) underinert atmosphere at 0° C.; warmed to RT and stirred for 1 h. To this wasadded 5-bromo-2-chloropyrimidine 592 (1 g, 0.51 mmol) at RT and stirredfor 4 h. The reaction was monitored by TLC; after completion thevolatiles were removed in vacuo to obtain the crude. The crude wasdiluted with ice-cold water (30 mL) and extracted with EtOAc (2×50 mL).The combined organic extracts were dried over sodium sulphate, filteredand concentrated in vacuo to afford compound 593 (900 mg, 92%). TLC: 10%EtOAc/hexanes (R_(f): 0.3); ¹H NMR (CDCl₃, 500 MHz): δ 8.59 (s, 2H),4.01 (s, 3H).

Synthesis of 2-methoxy-5-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) pyrimidine (594)

To a stirring solution of 5-bromo-2-methoxypyrimidine 593 (500 mg, 2.65mmol) in 1, 4-dioxane (25 mL) under inert atmosphere were added bispinacolato diboron (1.34 g, 5.29 mmol), potassium acetate (779 mg, 7.95mmol) at RT and stirred under argon atmosphere for 15 min. To this wasadded Pd(dppf)Cl₂ (193 mg, 0.26 mmol) and heated to 90-100° C. andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was filtered through celite, washedwith EtOAc (2×75 mL). The filtrate was concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 20-30% EtOAc/hexanes to afford compound 594 (700mg, crude). TLC: 20% EtOAc/hexanes (R_(f): 0.3); ¹H NMR (CDCl₃, 400MHz): δ 8.81 (s, 2H), 4.03 (s, 3H), 1.21 (s, 12H).

Synthesis of N-(4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl) cyclopropanecarboxamide (598)

Synthesis of N-(4-bromophenyl) cyclopropanecarboxamide (597)

To a stirring solution of 4-bromoaniline 595 (1 g, 5.81 mmol) in CH₂Cl₂(50 mL) under argon atmosphere were added diisopropylamine (2.1 mL,11.62 mmol), cyclopropanecarbonyl chloride 596 (604 mg, 5.81 mmol) at 0°C., warmed to RT and stirred for 2.5 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith saturated sodium bicarbonate solution (30 mL) and extracted withCH₂Cl₂ (25 mL). The organic layer was washed with water (30 mL) anddried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 40% EtOAc/hexanes to afford compound 597 (1.15 g,83%) as an off-white solid. TLC: 40% EtOAc/hexanes (R_(f): 0.3); ¹H NMR(DMSO-d₆, 400 MHz): δ 10.29 (s, 1H), 7.58-7.54 (m, 2H), 7.48-7.44 (m,2H), 1.79-1.72 (m, 1H), 0.82-0.78 (m, 4H); LC-MS: 99.73%; 239.7 (M⁺+1);(column; Kinetex EVO C-18, (50×3.0 mm, 2.6 μm); RT 2.71 min. 2.5 mM Aq.NH4OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of N-(4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl) cyclopropanecarboxamide (598)

To a stirring solution of N-(4-bromophenyl) cyclopropanecarboxamide 597(500 mg, 2.08 mmol) in 1, 4-dioxane (15 mL) under argon atmosphere wereadded bis pinacolato diboron (632 mg, 2.50 mmol), potassium acetate (510mg, 5.20 mmol) at RT in a sealed tube and purged under argon atmospherefor 15 min. To this was added Pd(dppf)Cl₂ (15 mg, 0.02 mmol) and purgedunder argon atmosphere for 10 min and heated to 110° C. and stirred for16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture diluted with water (20 mL) and extractedwith EtOAc (2×25 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using40% EtOAc/hexanes to afford compound 598 (520 mg, 87%) as an off-whitesolid. TLC: 40% EtOAc/hexanes (R_(f): 0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ10.28 (s, 1H), 7.61-7.58 (m, 4H), 1.83-1.74 (m, 1H), 1.28 (s, 12H),0.84-0.77 (m, 4H);

Synthesis of N-(4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl) acetamide (600)

Synthesis of N-(4-bromophenyl) acetamide (599)

To a stirring solution of 4-bromoaniline 595 (1 g, 5.81 mmol) in CH₂Cl₂(50 mL) under argon atmosphere were added trifluoroacetic acid (1.6 mL,11.62 mmol), acetic anhydride (0.6 mL, 5.81 mmol) at 0° C., warmed to RTand stirred for 2 h. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was diluted with water (50 mL) andextracted with CH₂Cl₂ (2×60 mL). The combined organic extracts werewashed with saturated sodium bicarbonate (50 mL), brine (50 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 40% EtOAc/hexanes to afford compound 599(1.1 g, 92%) as an off white solid. TLC: 40% EtOAc/hexanes (R_(f): 0.3);¹H NMR (DMSO-d₆, 400 MHz): δ 10.04 (br s, 1H), 7.57-7.53 (m, 2H),7.48-7.44 (m, 2H), 2.04 (s, 3H); LC-MS: 99.65%; 211.9 (M−1)⁺; (column;Kinetex EVO C-18, (50×3.0 mm, 2.6 μm); RT 2.21 min. 2.5 mM Aq.NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of N-(4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl) acetamide (600)

To a stirring solution of N-(4-bromophenyl) acetamide 599 (500 mg, 2.33mmol) in 1, 4-dioxane (15 mL) under argon atmosphere were added bispinacolato diboron (709 mg, 2.80 mmol), potassium acetate (572 mg, 5.84mmol) at RT and purged under argon atmosphere for 15 min. To this wasadded Pd(dppf)Cl₂ (17 mg, 0.02 mmol) and purged under argon atmospherefor 20 min and heated to 100° C. and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo to obtain the crude. The crude was purified throughsilica gel column chromatography using 40% EtOAc/hexanes to affordcompound 600 (510 mg, 84%) as an off-white solid. TLC: 40% EtOAc/hexanes(R_(f): 0.3); ¹H NMR (DMSO-d₆, 500 MHz): δ 10.02 (s, 1H), 7.60-7.58 (m,4H), 2.05 (s, 3H), 1.28 (s, 12H); LC-MS: 96.10%; 262 (M⁺+1); (column;Kinetex EVO C-18, (50×3.0 mm, 2.6 μm); RT 2.63 min. 2.5 mM Aq.NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of 1-(4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl) pyrrolidin-2-one (602)

Synthesis of 1-(4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl) pyrrolidin-2-one (602)

To a stirring solution of 1-(4-bromophenyl) pyrrolidin-2-one 601 (1 g,4.16 mmol) in 1, 4-dioxane:H₂O (10:1, 22 mL) in a sealed tube underinert atmosphere were added bis pinacolato diboron (1.27 g, 4.99 mmol),cesium carbonate (1.62 g, 4.99 mmol) at RT and purged under argonatmosphere for 15 min. To this was added Pd(dppf)Cl₂.CH₂Cl₂ (304 mg,0.41 mmol) and purged under argon atmosphere for 30 min, heated to 100°C. and stirred for 24 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 20% EtOAc/hexanes to afford compound 602 (800 mg,66%). TLC: 30% EtOAc/hexanes (R_(f): 0.3); LC-MS: 54.37%; 287.9 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.50 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of 6-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (604)

Synthesis of 6-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (604)

To a stirring solution of 6-bromo-3, 4-dihydroquinolin-2(1H)-one 603(500 mg, 2.21 mmol) in DMSO (25 mL) under inert atmosphere were addedbis pinacolato diboron (671 mg, 2.65 mmol), potassium acetate (650 mg,6.63 mmol) at RT and purged under argon atmosphere for 10 min. To thiswas added Pd(dppf)₂Cl₂ (161 mg, 0.22 mmol) and purged under argonatmosphere for 5 min; heated to 90° C. and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with EtOAc (100 mL), washed ice-cold water(2×30 mL), brine (30 mL). The organic extract was dried over sodiumsulphate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel flash column chromatography using20-30% EtOAc/hexanes to afford compound 604 (300 mg, crude) assemi-solid. TLC: 30% EtOAc/hexanes (R_(f): 0.3); ¹H NMR (DMSO-d₆, 400MHz): δ 10.21 (s, 1H), 7.50-7.39 (m, 2H), 6.83 (d, J=7.8 Hz, 1H),2.92-2.84 (m, 2H), 2.46-2.42 (m, 2H), 1.27 (s, 12H).

Synthesis of 5-fluoro-2-lithium tri isopropyl borate salt (606)

Synthesis of 5-fluoro-2-lithium tri isopropyl borate salt (606)

To a stirring solution of 2-bromo-5-fluoropyridine 605 (500 mg, 2.84mmol) and triisopropyl borate (0.8 mL, 3.4 mmol) in dry toluene (10 mL),dry THF (2 mL) under inert atmosphere was added n-butyl lithium (2.5 Msolution in hexane, 2.3 mL, 5.68 mmol) drop wise for 1.5 h at −78° C.and stirred for 30 min and warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo to obtain the crude, which washed withhexane (2×10 mL) to afford compound 606 (800 mg salt, crude) as brownsolid. This crude salt was taken up for the next reaction withoutpurification. TLC: 10% EtOAc/to hexanes (R_(f): 0.1);

Synthesis of 5-fluoro-2-lithium tri isopropyl borate salt (608)

Synthesis of 5-cyano-2-lithium triisopropyl borate salt (608)

To a stirring solution of 2-bromo-5-cyanopyridine 607 (1 g, 5.46 mmol)and triisopropyl borate (1.52 mL, 6.55 mmol) in dry toluene:dry THF(1:4; 25 mL) under inert atmosphere was added n-butyl lithium (2.5 Msolution in hexane, 3.4 mL, 5.46 mmol) drop wise for 1.5 h at −78° C.and stirred for 30 min and warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo to obtain the crude, which washed withhexane (2×10 mL) to afford compound 608 (1.6 g salt, crude) as yellowsolid. The crude was taken forward next reaction without furtherpurification. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2).

Synthesis of 2-(tributylstannyl) thiazole (610)

Synthesis of 2-(tributylstannyl) thiazole (610)

To a stirring solution of 2-bromothiazole 609 (5 g, 30.48 mmol) indiethyl ether (50 mL) under inert atmosphere was added n-butyl lithium(12.2 mL, 33.53 mmol, 2.5 M solution in hexane) dropwise for 15 min at−70° C. and stirred for 30 min. To this a solution of tributyltinchloride (10 mL, 30.48 mmol) in diethyl ether (15 mL) was added dropwisefor 10 min at −70° C. and stirred at the same temperature for 4 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (50 mL) and extracted withdiethylether (3×50 mL), washed with saturated potassium fluoridesolution (50 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to afford crude compound 610(11 g) as brown color syrup. The crude was carried forward for next stepwithout further purification. TLC: 30% EtOAc/hexanes (R_(f): 0.2); ¹HNMR (CDCl₃, 400 MHz): δ 8.17 (d, J=3.0 Hz, 1H), 7.54 (d, J=3.0 Hz, 1H),1.58-1.50 (m, 6H), 1.34-1.27 (m, 6H), 1.16-1.10 (m, 6H), 0.89-0.83 (m,9H) (NMR shows excess of tin reagent as impurity in the aliphaticregion).

Synthesis of 5-(tributylstannyl) thiazole (611)

To a stirring solution of 2-bromothiazole 609 (5 g, 30.48 mmol) indiethyl ether (35 mL) under inert atmosphere was added n-butyl lithium(12.2 mL, 33.53 mmol, 2.5 M solution in hexane) at −70° C. and stirredfor 30 min. To this was added a solution of tributyltin chloride (10 mL,30.48 mmol) in diethyl ether (15 mL) dropwise for 10 min at −70° C. andstirred at the same temperature for 4 h; warmed to RT and stirred for 2h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was diluted with water (100 mL) and extracted withdiethylether (3×50 mL) and washed with saturated potassium fluoridesolution (50 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through column chromatography using 25-30%EtOAc/hexanes to afford compound 611 (3.5 g, 31%) as white solid. TLC:30% EtOAc/hexanes (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 9.35 (s,1H), 7.89 (s, 1H), 1.58-1.47 (m, 6H), 1.34-1.24 (m, 6H), 1.13 (t, J=8.0Hz, 6H), 0.85 (t, J=7.3 Hz, 9H).

Synthesis of 5-methoxy-2-(tributylstannyl) pyridine (613)

Synthesis of 5-methoxy-2-(tributylstannyl) pyridine (613)

To a stirring solution of 2-bromo-5-methoxypyridine 612 (2 g, 10.64mmol) in THF (25 mL) under inert atmosphere was added n-butyl lithium(8.9 mL, 10.64 mmol, 1.6 M solution in hexane) at −78° C. and stirredfor 30 min. To this was added tributyltin chloride (3.5 g, 10.64 mmol)drop wise for 10 min at −78° C.; warmed to RT and stirred for 2 h;warmed to RT and stirred for 2 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was quenched withsaturated ammonium chloride (100 mL) and extracted with EtOAc (3×75 mL).The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude was purifiedthrough neutral alumina column chromatography using 10% EtOAc/hexanes toafford compound 613 (3 g) as pale yellow liquid. TLC: 10% EtOAc/hexanes(R_(f): 0.5); LC-MS: 75.23%; 400.1 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 2.56 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 4-fluoro-2-(tributylstannyl) pyridine (615)

Synthesis of 4-fluoro-2-(tributylstannyl) pyridine (615)

To a stirring solution of 2-bromo-4-fluoropyridine 614 (300 mg, 1.70mmol) in toluene (10 mL) under inert atmosphere was added n-butyllithium (1.2 mL, 2.04 mmol, 1.6 M solution in hexane) at −78° C. andstirred for 75 min. To this was added tributyltin chloride (0.55 mL,2.04 mmol) drop wise for 10 min at −78° C. and stirred at the sametemperature for 30 min; warmed to RT and stirred for 30 min. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was quenched with saturated ammonium chloride solution(100 mL) and extracted with EtOAc (2×15 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to afford compound 615 (700 mg, crude) as colorless syrup. TLC:10% EtOAc/hexanes (R_(f): 0.8); ¹H NMR (DMSO-d₆, 400 MHz): δ 9.35 (s,1H), 7.89 (s, 1H), 1.58-1.47 (m, 6H), 1.34-1.24 (m, 6H), 1.13 (t, J=8.0Hz, 6H), 0.85 (t, J=7.3 Hz, 9H).

Synthesis of 2-(trimethylstannyl) isonicotinonitrile (617)

Synthesis of 2-(trimethylstannyl) isonicotinonitrile (617)

To a stirring solution of 2-bromoisonicotinonitrile 616 (1.3 g, 7.10mmol) in toluene (20 mL) under argon atmosphere was added hexamethylditin (1.7 mL, 8.52 mmol) at RT and purged under argon atmosphere for 20min, added Pd(PPh₃)₄ (410 mg, 0.35 mmol) purged under argon atmospherefor 15 min; heated to 100° C. and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas filtered through celite, eluted with EtOAc (50 mL). The filtrate wasconcentrated in vacuo to afford crude compound 617 (2 g) as brown syrupwhich was carried forward for next step without further purification.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.3).

Preparation

Compound 535, 536, 538 & 539 was synthesized as mentioned above andconverted to final products through displacement reaction or crosscoupling reaction employing typical procedures D, E, F, G, H, I, J and Kand the results are captured in the Table 2:

Typical Procedure D:

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide536 (150 mg, 0.34 mmol) in 1, 2 dimethoxy ethane:H₂O (4:1, 8 mL) wereadded sodium carbonate (124 mg, 1.17 mmol), (3-chloro-4-hydroxyphenyl)boronic acid 556 (80.4 mg, 0.46 mmol) and purged under argon atmospherefor 20 min. To this was added Pd(dppf)Cl₂ (45 mg, 0.039 mmol) at RT;heated to 100-110° C. and stirred for 16 h. The reaction was monitoredby TLC; after completion the volatiles were removed in vacuo to obtainthe crude. The crude was either directly dried in vacuo or triturated orpurified through silica gel column chromatography to afford the desiredcompound.

Typical Procedure E:

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide536 (150 mg, 0.34 mmol) in 1, 4 dioxane:H₂O (3:1, 10 mL) were addedcesium carbonate (341 mg, 1.04 mmol), (3-fluoro-4-hydroxyphenyl) boronicacid 555 (54 mg, 0.34 mmol) and purged under argon atmosphere for 15min. To this was added Pd(dppf)Cl₂ (27 mg, 0.034 mmol) at RT; heated to100° C. and stirred for 16 h. The reaction was monitored by TLC; aftercompletion the volatiles were removed in vacuo to obtain the crude. Thecrude was either directly dried in vacuo or triturated or purifiedthrough silica gel column chromatography to afford the desired compound.

Typical Procedure F:

A mixture of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, 1] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide536 (100 mg, 0.23 mmol) and piperidine 472 (2 mL) in a sealed tube washeated to 120° C. and stirred for 4 h. The reaction was monitored byTLC; after completion the volatiles were removed in vacuo to obtain thecrude. The crude was either directly dried in vacuo or triturated orpurified through silica gel column chromatography to afford the desiredcompound.

Typical Procedure G:

To a solution of mixture N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide536 (150 mg, 0.34 mmol) in N-methyl pyrrolidinone (5 mL) were addedazepan-3-ol hydrochloride 503 (57.7 mg, 0.39 mmol) anddiisopropylethylamine (0.23 mL, 1.73 mmol) in a sealed tube and heatedto 160° C. and stirred for 24 h. The reaction was monitored by TLC andLC-MS; after completion the reaction mixture was diluted with water (50mL) and extracted with 10% MeOH/CH₂Cl₂ (2×50 mL). The combined organicextracts were dried over sodium sulphate, filtered and concentrated invacuo to obtain the crude. The crude was either directly dried in vacuoor triturated or purified through silica gel column chromatography toafford the desired compound.

Typical Procedure H:

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide536 (250 mg, 0.57 mmol) in 1,4-dioxane (20 mL) under argon atmosphere ina sealed tube were added 5-(tributylstannyl) thiazole 611 (324 mg, 0.86mmol) at RT and purged under argon atmosphere for 15 min; to this wasadded Pd(dppf)Cl₂ (42.2 mg, 0.057 mmol) at RT; heated to 110° C. andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was filtered through celite, washedwith 20% MeOH/CH₂Cl₂ (2×80 mL). The filtrate was concentrated in vacuoto obtain the crude. The crude was purified through silica gel flashcolumn chromatography using 10-12% EtOAc/hexanes and further purified bypreparative HPLC purification to afford the desired compound.

Typical Procedure I:

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide536 (100 mg, 0.23 mmol) in DMF (10 mL) under argon atmosphere in asealed tube were added 4-fluoro-1H-pyrazole 541 (40 mg, 0.46 mmol),cesium carbonate (150 mg, 0.46 mmol) at RT in a sealed tube and heatedto 110° C. and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, after completion the reaction mixturewas diluted with water (50 mL) and extracted with EtOAc (2×40 mL). Thecombined organic extracts were dried over sodium sulphate, filtered andconcentrated in vacuo to obtain the crude. The crude was either directlydried in vacuo or triturated or purified through silica gel columnchromatography/flash column chromatography to afford the desiredcompound.

Typical Procedure J:

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide536 (200 mg, 0.36 mmol) in 1, 4-dioxane (20 mL) under argon atmospherewas added cesium carbonate (450 mg, 1.38 mmol) in sealed tube at RT andpurged under argon for 20 min. To this were added Pd₂(dba)₃ (23 mg,0.023 mmol), t-BuXphos (14 mg, 0.032 mmol), 3,3-dimethylpyrrolidine 554(137 mg, 1.38 mmol), at RT and purged under argon for 5 min; heated to100° C. and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was filtered throughcelite and eluted with EtOAc (2×30 mL). The filtrate was concentrated invacuo to obtain the crude. The crude was either directly dried in vacuoor triturated or purified through silica gel column chromatography toafford the desired compound.

Typical Procedure K:

To a stirring solution N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] oxazepine-8-carboxamide 536 (150 mg,0.38 mmol) in N-methyl-2-pyrrolidone (1 mL) under argon atmosphere wasadded N, N-dimethylpiperidin-4-amine 544 (46 mg, 0.46 mmol) in sealedtube at RT; heated to 100° C. and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with water (25 mL), the precipitated solid was filtered,washed with CH₃CN (5 mL), diethyl ether (10 mL) and dried in vacuo toafford to afford the desired compound.

TABLE 2 Synthesis from compound 535, 536, 538, 539 common intermediatesProce- dure, Inter- medi- ate, bor- onic acid or boro- Mass Mass nateRx. Spec. Spec. Example Structure esters Yield Found Calculated ¹H-NMR1624

D^(f),  535, 579 23 476.9 (M⁺ + 1); 476.06 for C₂₃H₁₆N₄O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.51 (t, J = 5.6 Hz, 1H), 9.08 (brs, 1H), 8.65 (d, J = 4.1 Hz, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.06 (d, J =8.3 Hz, 1H), 7.98 (td, J = 7.5, 1.0 Hz, 2H), 7.93-7.79 (m, 5H), 7.51(dd, J = 7.9, 4.8 Hz, 1H), 4.72 (d, J = 5.5 Hz, 2H); 1625

D^(f),  535, 580 10 476.9 (M⁺ + 1); 476.06 for C₂₃H₁₆N₄O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.52 (t, J = 5.5 Hz, 1H), 8.68 (d,J = 5.3 Hz, 2H), 8.06 (d, J = 8.2 Hz, 1H), 8.01-7.94 (m, 3H), 7.93-7.88(m, 1H), 7.88-7.80 (m, 5H), 4.73 (d, J = 5.7 Hz, 2H); 1626

D^(f),  535, 581 27 477.9 (M⁺ + 1); 476.06 for C₂₂H₁₅N₅O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.53 (s, 1H), 9.54 (t, J = 5.6 Hz, 1H), 9.26 (s,2H), 9.25 (s, 1H), 8.07 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 3H), 7.90(td, J = 7.5, 1.6 Hz, 1H), 7.87-7.80 (m, 3H), 4.74 (d, J = 5.6 Hz, 2H);1636

G^(d),  535, 544 63 526.0 (M⁺ + 1); 525.15 for C₂₅H₂₇N₅O₄S₂ ¹H-NMR (500MHZ, DMSO-d₆): δ 11.49 (br s, 1H), 9.26 (t, J = 5.6 Hz, 1H), 8.04 (d, J= 8.4 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.82 (m, 3H), 7.78 (dd, J = 8.4,1.4 Hz, 1H), 7.02 (s, 1H), 4.44 (d, J = 5.5 Hz, 2H), 3.83-3.79 (m, 2H),2.97-2.90 (m, 2H), 2.34-2.28 (m, 1H), 2.18 (br s, 6H), 1.81-1.77 (m,2H), 1.45-1.32 (m, 2H); 1637

D^(f),  535, 573 15 516.0 (M⁺ + 1); 515.07 for C₂₅H₁₇N₅O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 12.62 (d, J = 11.5 Hz, 1H), 11.48 (br s, 1H), 9.46(t, J = 5.1 Hz, 1H), 8.31 (br s, 1H), 8.12 (br s, 1H), 8.06 (d, J = 8.3Hz, 1H), 8.01- 7.95 (m, 2H), 7.93- 7.80 (m, 4H), 7.80- 7.54 (m, 3H),4.69 (d, J = 5.3 Hz, 2H);   1645-A

D^(a),  535, 308 19 521.0 (M⁺ + 1); 520.05 for C₂₄H₁₆N₄O₆S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (br s, 1H), 9.52 (t, J = 4.8 Hz, 1H), 8.31(d, J = 8.8 Hz, 2H), 8.15 (d, J = 8.9 Hz, 2H), 8.06 (d, J = 8.3 Hz, 1H),8.01-7.95 (m, 3H), 7.93-7.80 (m, 4H), 4.73 (d, J = 5.5 Hz, 2H);   1654-A

D^(a),  535, 225 40 501.0 (M⁺ + 1); 500.06 for C₂₅H₁₆N₄O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.51 (t, J = 5.8 Hz, 1H), 8.09-8.04 (m, 3H), 8.01- 7.79 (m, 9H), 4.72 (d, J = 5.6 Hz, 2H); 1664

E,  535, 555 14 509.9 (M⁺ + 1); 509.05 for C₂₄H₁₆FN₃O₅S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (br s, 1H), 10.43 (br s, 1H), 9.45 (t, J =5.8 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 7.6. 0.8 Hz, 2H),7.90 (td, J = 7.4, 1.2 Hz, 1H), 7.87-7.78 (m, 3H), 7.72 (s, 1H), 7.62(dd, J = 12.1, 1.9 Hz, 1H), 7.51 (dd, J = 8.7, 1.4 Hz, 1H), 7.02 (t, J =8.7 Hz, 1H), 4.66 (d, J = 5.5 Hz, 2H); 1665

E^(b),  535, 586 25 527.9 (M⁺ + 1); 527.04 for C₂₄H₁₅F₂N₃O₅S₂ ¹H-NMR(DMSO-d₆, 500 MHz): δ 11.52 (s, 1H), 10.79 (br s, 1H), 9.47 (t, J = 5.6Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.98 (t, J = 8.4 Hz, 2H), 7.93-7.79(m, 4H), 7.76 (s, 1H), 7.53 (d, J = 7.5 Hz, 2H), 4.67 (d, J = 5.2 Hz,2H); 1667

D^(b),  535, 556 10 525.9 (M⁺ + 1); 525.02 for C₂₄H₁₆ClN₃O₅S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (br s, 1H), 10.79 (br s, 1H), 9.46 (t, J =5.5 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.78 (m,5H), 7.72 (s, 1H), 7.65 (dd, J = 8.5, 2.1 Hz, 1H), 7.03 (d, J = 8.5 Hz,1H), 4.66 (d, J = 5.4 Hz, 2H); 1668

D^(d),  535, 574 44 525.9 (M⁺ + 1); 525.02 for C₂₄H₁₆ClN₃O₅S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.49 (s, 1H), 10.39 (s, 1H), 9.44 (t, J = 5.6 Hz,1H), 8.04 (d, J = 8.4 Hz, 1H), 7.99- 7.93 (m, 3H), 7.88 (t, J = 7.4 Hz,1H), 7.85- 7.78 (m, 4H), 6.93 (d, J = 2.3 Hz, 1H), 6.85 (dd, J = 8.8,2.2 Hz, 1H), 4.68 (d, J = 5.8 Hz, 2H); 1670

D^(b),  535, 557 19 510.0 (M⁺ + 1); 509.05 for C₂₄H₁₆FN₃O₅S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 10.46 (s, 1H), 9.44 (t, J = 5.8 Hz,1H), 8.05 (d, J = 8.3 Hz, 1H), 8.01- 7.95 (m, 3H), 7.93- 7.77 (m, 5H),6.77- 6.67 (m, 2H), 4.68 (d, J = 5.6 Hz, 2H);   1671-A

E^(b),  535, 594 51 507.9 (M⁺ + 1); 507.07 for C₂₃H₁₇N₅O₅S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.51 (t, J = 5.5 Hz, 1H), 9.06 (s,2H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.80 (m, 5H),4.70 (d, J = 5.6 Hz, 2H), 3.98 (s, 3H); 1672

D^(c),  535, 591 53 491.9 (M⁺ + 1); 491.07 for C₂₃H₁₇N₅O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.43 (t, J = 5.8 Hz, 1H), 8.41 (d,J = 2.4 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.78 (m,5H), 7.66 (s, 1H), 6.51- 6.44 (m, 3H), 4.64 (d, J = 5.6 Hz, 2H); 1673

D^(e),  535, 558 47 493.0 (M⁺ + 1); 492.07 for C₂₂H₁₆N₆O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.68 (s,2H), 8.05 (d, J = 8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.90 (td, J = 7.5, 1.5Hz, 1H), 7.88-7.79 (m, 3H), 7.72 (s, 1H), 7.19 (s, 2H), 4.66 (d, J = 5.8Hz, 2H); 1674

D^(l),  535, 588 6 520.0 (M⁺ + 1); 519.10 for C₂₅H₂₁N₅O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): ) δ 11.52 (s, 1H), 9.43 (br t, J = 5.6 Hz, 1H), 8.58(d, J = 2.3 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.01-7.79 (m, 7H), 7.68(s, 1H), 6.70 (d, J = 8.9 Hz, 1H), 4.65 (br d, J = 5.6 Hz, 2H), 3.08 (s,6H); 1675

D^(e),  535, 571 42 521.0 (M⁺ + 1); 520.10 for C₂₄H₂₀N₆O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.45 (t, J = 5.8 Hz, 1H), 8.79 (s,2H), 8.05 (d, J = 8.3 Hz, 1H), 7.98 (dd, J = 7.7, 1.1 Hz, 2H), 7.90 (td,J = 7.4, 1.4 Hz, 1H), 7.87-7.79 (m, 3H), 7.74 (s, 1H), 4.66 (d, J = 5.6Hz, 2H), 3.18 (s, 6H);   1677-A

D^(f),  535, 559 55 500.9 (M⁺ + 1); 500.06 for C₂₅H₁₆N₄O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.51 (t, J = 5.8 Hz, 1H), 8.30 (s,1H), 8.20 (dt, J = 8.3, 1.3 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.98 (dt,J = 7.5, 1.1 Hz, 2H), 7.94-7.79 (m, 6H), 7.69 (t, J = 7.8 Hz, 1H), 4.71(d, J = 5.6 Hz, 2H); 1972

F^(a),  535, 550 53 529.1 (M⁺ + 1); 528.11 for C₂₄H₂₄N₄O₆S ¹H NMR (400MHz, DMSO-d₆): δ = 11.50 (s, 1H), 9.25 (t, J = 5.7 Hz, 1H), 8.04 (d, J =8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.82 (m, 3H), 7.79 (dd, J = 8.3,1.4 Hz, 1H), 6.95 (s, 1H), 4.87 (d, J = 4.6 Hz, 2H), 4.42 (d, J = 5.6Hz, 2H), 3.74 (br s, 2H), 3.78-3.71 (m, 2H), 3.18-3.15 (m, 2H),1.81-1.79 (m, 2H), 1.40-1.20 (m, 2H);   1804-A

D,  535, 560 37 520.0 (M⁺ + 1); 519.09 for C₂₆H₂₁N₃O₅S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.52 (s, 1H), 9.45 (t, J = 5.6 Hz, 1H), 8.06 (d, J = 8.3Hz, 1H), 7.97 (dd, J = 7.3 1.1 Hz 2H), 7.93-7.79 (m, 4H), 7.72-7.65 (m,3H), 7.01 (d, J = 8.4 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H), 3.83 (s, 3H),2.19 (s, 3H); 1805

D,  535, 561 38 516.0 (M⁺ + 1); 515.07 for C₂₅H₁₇N₅O₄S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 13.26 (s, 1H), 11.52 (s, 1H), 9.47 (t, J = 5.9 Hz, 1H),8.31-8.28 (m, 1H), 8.16 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.00-7.95 (m,2H), 7.93-7.88 (m, 2H), 7.87 (s, 1H), 7.86-7.81 (m, 2H), 7.76 (s, 1H),7.61 (d, J = 8.8 Hz, 1H), 4.69 (d, J = 5.6 Hz, 2H);   1806-A

D^(g),  535, 562 40 534.0 (M⁺ + 1); 533.11 for C₂₇H₂₃N₃O₅S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06 (d,J = 8.3 Hz, 1H), 7.98 (td, J = 1.0, 7.3 Hz, 2H), 7.93-7.80 (m, 4H), 7.74(s, 1H), 7.55 (s, 2H), 4.67 (d, J = 5.5 Hz, 2H), 3.68 (s, 3H), 2.26 (s,6H); 1815

D,  535, 563 17 519.0 (M⁺ + 1); 518.05 for C₂₅H₁₅FN₄O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.53 (s, 1H), 9.53 (t, J = 5.8 Hz, 1H), 8.08-7.94 (m, 6H), 7.93- 7.80 (m, 5H), 4.73 (d, J = 5.6 Hz, 2H); 1816

D^(q),  535, 577 8 535.0 (M⁺ + 1); 534.02 for C₂₅H₁₅ClN₄O₄S₂ ¹H NMR(DMSO-d₆, 400 MHz): δ 11.51 (br s, 1H), 9.53 (t, J = 5.8 Hz, 1H), 8.36(d, J = 8.4 Hz, 1H), 8.26 (d, J = 1.5 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H),8.02 (s, 1H), 8.00-7.95 (m, 2H), 7.95-7.84 (m, 4H), 7.83-7.79 (m, 1H),4.76 (d, J = 5.6 Hz, 2H); 1817

D^(p),  535, 570 16 535.0 (M⁺ + 1); 534.02 for C₂₅H₁₅ClN₄O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (br s, 1H), 9.54 (t, J = 5.8 Hz, 1H), 8.19(s, 1H), 8.08-8.05 (m, 2H), 8.03-7.95 (m, 4H), 7.93-7.78 (m, 4H), 4.73(d, J = 5.6 Hz, 2H); 1819

D^(p),  535, 564 30 527.1 (M⁺ + 1); 526.08 for C₂₇H₁₈N₄O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.53 (s, 1H), 9.53 (t, J = 5.7 Hz, 1H), 8.93 (dd,J = 4.2, 1.7 Hz, 1H), 8.54 (s, 1H), 8.50 (dd, J = 8.5, 1.0 Hz, 1H), 8.28(dd, J = 8.8, 2.1 Hz, 1H), 8.08 (t, J = 7.8 Hz, 2H), 7.98 (td, J = 7.8,1.0 Hz, 2H), 7.94-7.81 (m, 5H), 7.59 (dd, J = 8.3, 4.2 Hz, 1H), 4.73 (d,J = 5.6 Hz, 2H); 1820

D^(p),  535, 565 17 527.1 (M⁺ + 1); 526.08 for C₂₇H₁₈N₄O₄S₂ ¹H NMR(DMSO-d₆, 400 MHz): δ 11.53 (br s, 1H), 9.54 (t, J = 5.8 Hz, 1H), 9.34(s, 1H), 8.56-8.50 (m, 2H), 8.23-8.18 (m, 2H), 8.07 (d, J = 8.3 Hz, 1H),8.01- 7.81 (m, 8H), 4.74 (d, J = 5.6 Hz, 2H); 1826

D^(r),  539, 575 16 471.6 (M⁺ + 1); 470.08 for C₂₅H₁₅FN₄O₃S ¹H NMR(DMSO-d₆, 400 MHz): δ = 10.63 (s, 1H), 9.27 (t, J = 5.8 Hz, 1H), 8.35(t, J = 7.9 Hz, 1H), 8.09 (dd, J = 11.3, 1.5 Hz, 1H), 8.01 (d, J = 2.4Hz, 1H), 7.84-7.77 (m, 2H), 7.70 (d, J = 2.0 Hz, 1H), 7.67- 7.60 (m,2H), 7.43 (d, J = 8.4 Hz, 1H), 7.39-7.30 (m, 2H), 4.72 (d, J = 5.6 Hz,2H); 1838

D^(o),  535, 566 61 506.0 (M⁺ + 1); 505.08 for C₂₅H₁₉N₃O₅S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.49 (t, J = 5.7 Hz, 1H), 8.06 (d,J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.94-7.80 (m, 5H), 7.69-7.63 (m,2H), 7.47 (td J = 7.6, 1.1 Hz, 1H), 7.39-7.34 (m, 1H), 5.31 (t, J = 5.9Hz, 1H), 4.79- 4.66 (m, 4H); 1855

D^(o),  535, 567 40 554.0 (M⁺ + 1); 553.04 for C₂₅H₁₉N₃O₆S₃ ¹H NMR(DMSO-d₆, 500 MHz): δ 11.58 (br s, 1H), 9.52 (t, J = 5.8 Hz, 1H), 8.18(d, J = 8.2 Hz, 2H), 8.10-8.04 (m, 1H), 8.01-7.94 (m, 4H), 7.92-7.82 (m,5H), 4.72 (d, J = 5.5 Hz, 2H), 3.23 (s, 3H); 1856

D^(o),  535, 576 11 555.0 (M⁺ + 1); 554.04 for C₂₄H₁₈N₄O₆S₃ ¹H NMR(DMSO-d₆, 400 MHz): δ 11.52 (br s, 1H), 9.52 (t, J = 5.8 Hz, 1H), 8.10-8.05 (m, 3H), 8.01- 7.95 (m, 2H), 7.93- 7.86 (m, 5H), 7.86- 7.80 (m,2H), 7.45 (s, 2H), 4.71 (d, J = 5.5 Hz, 2H); 1857

D^(o),  535, 568 22 569.1 (M⁺ + 1); 568.05 C₂₅H₂₀N₄O₆S₃ ¹H NMR (DMSO-d₆,400 MHz): δ 11.51 (br s, 1H), 10.08 (br s, 1H), 9.46 (t, J = 5.8 Hz,1H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.79 (m, 6H),7.75 (s, 1H), 7.27 (d, J = 8.7 Hz, 2H), 4.67 (d, J = 5.5 Hz, 2H), 3.05(s, 3H); 1860

J^(a),  535, 545 14 533.0 (M⁺ + 1); 532.05 for C₂₂H₂₀N₄O₆S₃ ¹H NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.31 (t, J = 5.7 Hz, 1H), 8.05 (d,J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.82 (m, 3H), 7.79 (d, J = 8.2Hz, 1H), 7.09 (s, 1H), 4.46 (d, J = 5.6 Hz, 2H), 3.90-3.84 (m, 4H),3.22-3.15 (m, 4H);   1879-A

H^(c),  535, 613 26 507.0 (M⁺ + 1); 506.07 for C₂₄H₁₈N₄O₅S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (br s, 1H), 9.44 (t, J = 5.5 Hz, 1H), 8.30(d, J = 2.6 Hz, 1H), 8.11-7.93 (m, 5H), 7.92-7.77 (m, 6H), 7.52 (dd, J =8.7, 2.8 Hz, 1H), 4.67 (d, J = 5.4 Hz, 2H), 3.88 (s, 3H); 1881

D^(s),  535, 608 26 542   (M⁺ + 1); 501.06 for C₂₄H₁₅N₅O₄S₂ ¹H NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.52 (t, J = 5.7 Hz, 1H), 9.05 (d,J = 1.2 Hz, 1H), 8.42 (dd, J = 8.3, 2.1 Hz, 1H), 8.22 (d, J = 8.2 Hz,1H), 8.06 (d, J = 8.2 Hz, 1H), 8.01- 7.95 (m, 3H), 7.93- 7.79 (m, 4H),4.73 (d, J = 5.6 Hz, 2H); 1905

F,  535, 472 68 483.1 (M⁺ + 1); 482.11 for C₂₃H₂₂N₄O₄S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.50 (s, 1H), 9.25 (t, J = 5.2 Hz, 1H), 8.04 (d, J = 8.2Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.81 (m, 3H), 7.78 (d, J = 8.4 Hz, 1H),7.01 (s, 1H), 4.44 (d, J = 5.4 Hz, 2H), 3.35-3.30 (m, 4H), 1.56-1.52 (m,6H); 1907

G^(b),  535, 540 26 497.1 (M⁺ + 1); 496.12 for C₂₄H₂₄N₄O₄S₂ ¹H NMR (400MHz, DMSO-d₆): δ 11.50 (s, 1H), 9.23 (t, J = 5.6 Hz, 1H), 8.04 (d, J =8.2 Hz, 1H), 8.00-7.95 (m, 2H), 7.92-7.81 (m, 3H), 7.79 (dd, J = 8.3,1.4 Hz, 1H), 4.43 (d, J = 5.6 Hz, 2H), 3.48- 3.43 (m, 4H), 1.74- 1.66(m, 4H), 1.52- 1.43 (m, 4H); 1908

G,  535, 503 28 513.1 (M⁺ + 1); 512.12 for C₂₄H₂₄N₄O₅S₂ ¹H NMR (400 MHz,DMSO-d₆): δ 11.50 (s, 1H), 9.24 (br t, J = 5.6 Hz, 1H), 8.04 (d, J = 8.3Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.82 (m, 3H), 7.79 (dd, J = 8.3, 1.3Hz, 1H), 6.96 (s, 1H), 4.83 (d, J = 4.4 Hz, 1H), 4.43 (br d, J = 5.5 Hz,2H), 3.81- 3.66 (m, 2H), 3.52- 3.43 (m, 1H), 3.40- 3.35 (m, 1H), 3.20-3.10 (m, 1H), 1.85- 1.56 (m, 4H), 1.48- 1.36 (m, 1H), 1.29- 1.17 (m,1H); 1858

D^(p),  535, 602 26 559.1 (M⁺ + 1); 558.10 for C₂₈H₂₂N₄O₅S₂ 1H-NMR(DMSO- d6, 400 MHz): δ 11.42 (br s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 8.06(d, J = 8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.75 (m, 9H), 4.68 (d, J =5.6 Hz, 2H), 3.86 (t, J = 7.1 Hz, 2H), 2.52- 2.50 (m, 2H), 2.12- 2.03(m, 2H); 1859

G^(c),  535, 485 10 499.1 (M⁺ + 1); 498.10 for C₂₃H₂₂N₄O₅S₂ 1H NMR(DMSO- d6, 400 MHz): δ 11.50 (s, 1H), 9.25 (t, J = 5.6 Hz, 1H),8.05-7.95 (m, 3H), 7.93-7.82 (m, 3H), 7.78 (d, J = 8.3 Hz, 1H), 7.01 (s,1H), 4.74 (br s, 1H), 4.44 (d, J = 5.5 Hz, 2H), 3.72-3.58 (m, 3H),3.15-3.06 (m, 2H), 1.79-1.74 (m, 2H), 1.44-1.34 (m, 2H); 1864

D^(p),  539, 602 18 511.2 (M⁺ + 1); 510.14for C₂₈H₂₂N₄O₄S 1H NMR ((DMSO-d6, 400 MHz): δ 10.64 (s, 1H), 9.21 (t, J = 5.8 Hz, 1H), 7.90-7.86 (m,2H), 7.80-7.74 (m, 4H), 7.70 (d, J = 2.0 Hz, 1H), 7.66-7.60 (m, 2H),7.43 (d, J = 8.4 Hz, 1H), 7.39-7.30 (m, 2H), 4.65 (d, J = 5.6 Hz, 2H),3.86 (t, J = 7.0 Hz, 2H), 2.52-2.50 (m, 2H), 2.07 (p, J = 7.5 Hz, 2H);1930

D^(o),  535, 569 27 531.0 (M⁺ + 1); 530.07 for C₂₆H₁₈N₄O₅S₂ ¹H NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.98 (s, 1H), 9.50 (t, J = 5.8 Hz,1H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.80 (m, 5H),7.57-7.54 (m, 1H), 7.31 (d, J = 7.3 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H),4.71 (d, J = 5.5 Hz, 2H), 3.61 (s, 2H); 1931

D^(p),  535, 598 16 559.1 (M⁺ + 1); 558.10 C₂₈H₂₂N₄O₅S₂ ¹H NMR (DMSO-d₆,400 MHz): δ 11.51 (br s, 1H), 10.40 (s, 1H), 9.45 (t, J = 5.8 Hz, 1H),8.05 (d, J = 8.2 Hz, 1H), 8.00- 7.95 (m, 2H), 7.92- 7.78 (m, 6H), 7.74(s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 4.67 (d, J = 5.6 Hz, 2H), 1.84- 1.76(m, 1H), 0.84- 0.79 (m, 4H); 1932

D^(p),  535, 600 38 533.1 (M⁺ + 1); 532.09 C₂₆H₂₀N₄O₅S₂ ¹H NMR (DMSO-d₆,400 MHz): δ 11.51 (s, 1H), 10.14 (s, 1H), 9.45 (t, J = 5.7 Hz, 1H), 8.06(d, J = 8.3 Hz, 1H), 8.00- 7.95 (m, 2H), 7.93- 7.84 (m, 3H), 7.83- 7.79(m, 3H), 7.74 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 4.67 (d, J = 5.5 Hz,2H), 2.06 (s, 3H); 1951

D^(i),  535, 604 56 545.1 (M⁺ + 1); 544.09 for C₂₇H₂₀N₄O₅S₂ ¹H NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 10.29 (s, 1H), 9.46 (t, J = 5.7 Hz,1H), 8.06 (d, J = 8.3 Hz, 1H), 8.00- 7.95 (m, 2H), 7.93- 7.80 (m, 4H),7.73- 7.64 (m, 3H), 6.91 (d, J = 8.3 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H),2.94 (t, J = 7.5 Hz, 2H), 2.48-2.46 (m, 2H); 1953

D,  538, 578 27 542.0 (M⁺ + 1); 541 for C₂₇H₁₉N₅O₄S₂ ¹H NMR (DMSO-d₆,400 MHz): δ 13.45- 12.95 (m, 1H), 11.52 (br s, 1H), 9.49 (t, J = 4.8 Hz,1H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.94-7.90 (m, 4H),7.89-7.83 (m, 4H), 7.82-7.80 (m, 2H), 6.78 (s, 1H), 4.70 (d, J = 5.3 Hz,2H); 1954

H^(d),  538, 610 20 559.0 (M⁺ + 1); 558 for C₂₇H₁₈N₄O₄S₃ 1H NMR (DMSO-d6, 400 MHz): δ 11.51 (br s, 1H), 9.50 (t, J = 5.7 Hz, 1H), 8.08-8.04(m, 3H), 8.03-7.95 (m, 5H), 7.93-7.80 (m, 6H), 4.71 (d, J = 5.6 Hz, 2H);1959

D^(d),  535, 578 11 466.0 (M⁺ + 1); 465.06 C₂₁H₁₅N₅O₄S₂ 1H NMR DMSO-d6,400 MHz): δ 13.16 (br s, 1H), 11.51 (s, 1H), 9.43 (br t, J = 5.8 Hz,1H), 8.05 (d, J = 8.3 Hz, 1H), 7.98 (td, J = 7.7, 1.1 Hz, 2H), 7.93-7.79(m, 5H), 7.70 (s, 1H), 6.69 (t, J = 2.1 Hz, 1H), 4.65 (d, J = 5.8 Hz,2H); 1956

H,  535, 611 6 483.0 (M⁺ + 1); 482.02 for C₂₁H₁₄N₄O₄S₃ ¹H NMR (DMSO-d₆,400 MHz): δ 11.52 (br s, 1H), 9.50 (t, J = 5.8 Hz, 1H), 9.17 (s, 1H),8.42 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.01-7.96 (m, 2H), 7.90 (td, J =7.5, 1.5 Hz, 1H), 7.87-7.80 (m, 3H), 7.78 (s, 1H), 4.68 (d, J = 5.6 Hz,2H); 1960

K^(a),  535, 453 56 466.3 (M⁺ + 1); 465.06 for C₂₁H₁₅N₅O₄S₂ ¹H NMR(DMSO-d₆, 500 MHz): δ 11.52 (s, 1H), 9.48 (t, J = 5.5 Hz, 1H), 8.46 (d,J = 2.9 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.99 (t, J = 8.7 Hz, 2H),7.94-7.80 (m, 5H), 7.55 (s, 1H), 6.61 (d, J = 1.7 Hz, 1H), 4.62 (d, J =5.8 Hz, 2H); 1981

J,  535, 554 35 497.0 (M⁺ + 1); 496.12 for C₂₄H₂₄N₄O₄S₂ ¹H NMR (DMSO-d₆,400 MHz): δ 11.50 (s, 1H), 9.24 (t, J = 5.7 Hz, 1H), 8.04 (d, J = 8.2Hz, 1H), 8.00-7.95 (m, 2H), 7.92-7.82 (m, 3H), 7.78 (dd, J = 8.3, 1.4Hz, 1H), 6.99 (s, 1H), 4.43 (d, J = 5.5 Hz, 2H), 3.38 (t, J = 6.9 Hz,2H), 3.08 (s, 2H), 1.75 (t, J = 7.0 Hz, 2H), 1.06 (s, 6H); 11038 

I,  535, 541 48 483.9 (M⁺ + 1); 483.05 for C₂₁H₁₄FN₅O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.48 (t, J = 5.6 Hz, 1H), 8.64 (d,J = 4.1 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.01-7.95 (m, 3H), 7.93-7.78(m, 4H), 7.55 (s, 1H), 4.61 (br d, J = 5.6 Hz, 2H); 11039 

I^(a),  535, 542 46 534.0 (M⁺ + 1); 533.04 for C₂₂H₁₄F₃N₅O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.51 (t, J = 5.6 Hz, 1H), 9.16 (s,1H), 8.32 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.98 (td, J = 7.5, 1.2 Hz,2H), 7.93-7.84 (m, 3H), 7.81 (td, J = 4.9, 1.5 Hz, 1H), 7.65 (s, 1H),4.64 (d, J = 5.5 Hz, 2H); 11040 

D^(t),  535, 606 9 495   (M⁺ + 1); 494.05 for C₂₃H₁₅FN₄O₄S₂ ¹H NMR(DMSO-d₆, 400 MHz): δ 11.49 (s, 1H), 9.45 (t, J = 5.9 Hz, 1H), 8.59 (d,J = 2.9 Hz, 1H), 8.12 (dd, J = 8.8, 4.6 Hz, 1H), 8.03 (d, J = 8.2 Hz,1H), 7.98-7.93 (m, 2H), 7.90-7.76 (m, 6H), 4.66 (d, J = 5.6 Hz, 2H);11045 

I,  535, 543 18 483.9 (M⁺ + 1); 483.05 for C₂₁H₁₄FN₅O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.48 (t, J = 5.6 Hz, 1H), 8.44 (d,J = 2.9 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.98 (t, J = 6.9 Hz, 2H),7.94-7.77 (m, 4H), 7.54 (s, 1H), 6.46 (dd, J = 5.3, 2.7 Hz, 1H), 4.61(d, J = 5.5 Hz, 2H); 11049 

H,  535, 584 19 483.1 (M⁺ + 1); 482.02 for C₂₁H₁₄N₄O₄S₃ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.51 (s, 1H), 9.46 (t, J = 5.8 Hz, 1H), 9.20 (d, J = 2.0Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.98 (td, J= 1.3, 8.3 Hz, 2H), 7.94-7.84 (m, 3H), 7.847.79 (m, 2H), 4.69 (d, J =5.8 Hz, 2H); 11050 

H^(a),  535, 615 17 495.0 (M⁺ + 1); 494.05 for C₂₃H₁₅FN₄O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.49 (t, J = 5.7 Hz, 1H), 8.64 (dd,J = 8.4, 5.6 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.01-7.95 (m, 2H),7.93-7.78 (m, 6H), 7.45-7.39 (m, 1H), 4.71 (d, J = 5.8 Hz, 2H); 11051 

H^(b),  535, 617 18 502.0 (M⁺ + 1); 501.06 for C₂₄H₁₅N₅O₄S₂ ¹H NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.51 (t, J = 5.7 Hz, 1H), 8.84 (dd,J = 5.0, 0.8 Hz, 1H), 8.39 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.01-7.94(m, 3H), 7.94-7.90 (m, 2H), 7.89-7.84 (m, 2H), 7.81 (dd, J = 8.2, 1.4Hz, 1H), 4.72 (d, J = 5.6 Hz, 2H); 11150 

D^(t),  536, 606 20 509.1 (M⁺ + 1); 508.07 for C₂₄H₁₇FN₄O₄S₂ ¹H NMR(DMSO-d₆, 400 MHz): δ 10.85 (s, 1H), 9.21 (t, J = 5.8 Hz, 1H), 8.65 (d,J = 2.8 Hz, 1H), 8.16 (dd, J = 8.8, 4.6 Hz, 1H), 7.96-7.83 (m, 6H),7.82-7.76 (m, 1H), 7.36 (d, J = 8.2 Hz, 1H), 4.66 (d, J = 6.0 Hz, 2H),2.32 (s, 3H); 11152 

D,  536, 578 34 480.1 (M⁺ + 1); 479.07 for C₂₂H₁₇N₅O₄S₂ ¹H NMR (DMSO-d₆,400 MHz): δ 10.85 (s, 1H), 9.16 (t, J = 5.8 Hz, 1H), 7.94- 7.90 (m, 2H),7.89- 7.84 (m, 3H), 7.82- 7.77 (m, 1H), 7.70 (s, 1H), 7.35 (d, J = 8.2Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 4.63 (d, J = 5.9 Hz, 2H), 2.32 (s,3H); 11148 

I^(b),  536, 541 23 498.0 (M⁺ + 1); 497.06 for C₂₂H₁₆FN₅O₄S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 10.87 (s, 1H), 9.21 (t, J = 5.8 Hz, 1H), 8.67 (d,J = 4.1 Hz, 1H), 8.00 (d, J = 4.0 Hz, 1H), 7.94-7.89 (m, 2H), 7.89-7.84(m, 2H), 7.79 (td, J = 7.8, 1.6 Hz, 1H), 7.55 (s, 1H), 7.35 (d, J = 8.2Hz, 1H), 4.58 (d, J = 5.8 Hz, 2H), 2.32 (s, 3H); 11149 

I^(b),  536, 542 19 548.1 (M⁺ + 1); 547.06 for C₂₃H₁₆F₃N₅O₄S₂ ¹H NMR(400 MHz, DMSO-d₆) δ 10.87 (br s, 1H), 9.25 (t, J = 5.3 Hz, 1H), 9.18(s, 1H), 8.34 (s, 1H), 8.00-7.75 (m, 5H), 7.64 (s, 1H), 7.36 (d, J = 8.0Hz, 1H), 4.61 (d, J = 5.3 Hz, 2H), 2.32 (s, 3H); 1694

K,  539, 305 23 450.0 (M⁺ + 1) 934.28 for C₄₆H₄₇ClN₁₀O₆S₂ ¹H-NMR(DMSO-d₆, 500 MHz): δ 10.62 (s, 1H), 9.01 (t, J = 5.8 Hz, 1H), 7.78 (dd,J = 7.8, 1.4 Hz, 1H), 7.68-7.58 (m, 3H), 7.41 (d, J = 8.4 Hz, 1H),7.38-7.31 (m, 2H), 7.03 (s, 1H), 4.42 (d, J = 5.8 Hz, 2H), 3.34-3.29 (m,4H), 2.44-2.37 (m, 4H), 2.22 (br s, 3H); 1695

E,  539, 573 14 468.0 (M⁺ + 1); 467.11 for C₂₅H₁₇N₅O₃S ¹H-NMR (DMSO-d₆,400 MHz): δ 10.64 (s, 1H), 9.23 (t, J = 5.3 Hz, 1H), 8.66 (br s, 1H),8.14 (s, 1H), 7.84 (br d, J = 8.7 Hz, 1H), 7.80-7.69 (m, 5H), 7.66-7.60(m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.39- 7.31 (m, 2H), 4.67 (br d, J =5.5 Hz, 2H); 1696

D^(f),  539, 572 41 467.0 (M⁺ + 1); 466.11 C₂₆H₁₈N₄O₃S ¹H-NMR (DMSO-d₆,400 MHz): δ 11.31 (br s, 1H), 10.64 (s, 1H), 9.19 (t, J = 5.7 Hz, 1H),8.08 (s, 1H), 7.78 (dd, J = 7.7, 1.7 Hz, 1H), 7.71-7.69 (m, 2H),7.66-7.61 (m, 3H), 7.46-7.40 (m, 3H), 7.38-7.31 (m, 2H), 6.52 (t, J =2.1 Hz, 1H), 4.64 (d, J = 5.6 Hz, 2H); 1700

E^(c),  539, 555 8 461.9 (M⁺ + 1); 461.08 for C₂₄H₁₆FN₃O₄S ¹H-NMR(DMSO-d₆, 400 MHz): δ 10.64 (s, 1H), 10.50 (br s, 1H), 9.19 (t, J = 5.8Hz, 1H), 7.78 (dd, J = 7.7, 1.6 Hz, 1H), 7.71-7.69 (m, 2H), 7.66-7.59(m, 3H), 7.51 (dd, J = 8.4, 1.5 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.38-7.30 (m, 2H), 7.00 (t, J = 8.7 Hz, 1H), 4.63 (br d, J = 5.6 Hz, 2H);1701

E^(b),  539, 586 30 479.9 (M⁺ + 1); 479.08 for C₂₄H₁₅F₂N₃O₄S ¹H-NMR(DMSO-d₆, 400 MHz): δ 10.65 (s, 1H), 9.21 (t, J = 5.6 Hz, 1H), 7.82 (d,J = 8.1 Hz, 1H), 7.40-7.31 (m, 4H), 7.70-7.60 (m, 5H), 4.67 (d, J = 5.2Hz, 2H); 1702

D^(b),  539, 556 64 477.9 (M⁺ + 1); 477.06 for C₂₄H₁₆ClN₃O₄S ¹H-NMR(DMSO-d₆, 500 MHz): δ 10.78 (br s, 1H), 10.64 (s, 1H), 9.21 (t, J = 5.5Hz, 1H), 7.83-7.76 (m, 2H), 7.72-7.60 (m, 5H), 7.42 (d, J = 8.4 Hz, 1H),7.38- 7.31 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 4.63 (d, J = 5.5 Hz, 2H);1703

D^(p),  539, 574 62 477.9 (M⁺ + 1); 477.06 for C₂₄H₁₆ClN₃O₄S ¹H-NMR(DMSO-d₆, 400 MHz): δ 10.64 (s, 1H), 10.41 (s, 1H), 9.21 (t, J = 5.7 Hz,1H), 7.97 (d, J = 8.8 Hz, 1H), 7.80- 7.76 (m, 2H), 7.69 (s, 1H),7.66-7.60 (m, 2H), 7.43 (d, J = 8.3 Hz, 1H), 7.38-7.31 (m, 2H), 6.94 (d,J = 2.5 Hz, 1H), 6.87 (dd, J = 8.8, 2.4 Hz, 1H), 4.67 (d, J = 5.6 Hz,2H); 1704

D^(b),  539, 557 13 461.9 (M⁺ + 1); 461.08 for C₂₄H₁₆FN₃O₄S ¹H-NMR(DMSO-d₆, 500 MHz): δ 10.62 (s, 1H), 10.45 (s, 1H), 9.19 (t, J = 5.8 Hz,1H), 7.98 (t, J = 9.0 Hz, 1H), 7.80- 7.74 (m, 2H), 7.69 (d, J = 2.0 Hz,1H), 7.65-7.60 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.38-7.31 (m, 2H),6.77-6.67 (m, 2H), 4.65 (d, J = 5.5 Hz, 2H); 1708

D^(j),  539, 588 25 472.0 (M⁺ + 1); 471.14 for C₂₅H₂₁N₅O₃S ¹H NMR(DMSO-d₆, 500 MHz): δ 10.63 (s, 1H), 9.17 (t, J = 5.6 Hz, 1H), 8.58 (d,J = 2.0 Hz, 1H), 7.92 (dd, J = 9.0, 2.3 Hz, 1H), 7.78 (d, J = 7.2 Hz,1H), 7.70-7.59 (m, 4H), 7.42 (d, J = 8.4 Hz, 1H), 7.39- 7.31 (m, 2H),6.70 (d, J = 9.0 Hz, 1H), 4.62 (br d, J = 5.5 Hz, 2H), 3.08 (s, 6H);  1709-A

D^(i),  539, 594 27 460.0 (M⁺ + 1); 459.10 for C₂₃H₁₇N₅O₄S ¹H NMR(DMSO-d₆, 400 MHz): δ 10.64 (s, 1H), 9.25 (t, J = 5.8 Hz, 1H), 9.06 (s,2H), 7.85 (s, 1H), 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.70 (d, J = 2.1 Hz,1H), 7.66- 7.60 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.39-7.31 (m, 2H),4.68 (d, J = 5.6 Hz, 2H), 3.98 (s, 3H); 1710

E^(a),  539, 558 6 445.0 (M⁺ + 1); 444.10 for C₂₂H₁₆N₆O₃S ¹H-NMR(DMSO-d₆, 400 MHz): δ 10.63 (s, 1H), 9.20 (t, J = 5.8 Hz, 1H), 8.68 (s,2H), 7.78 (dd, J = 7.7, 1.6 Hz, 1H), 7.73-7.68 (m, 2H), 7.66-7.59 (m,2H), 7.42 (d, J = 8.3 Hz, 1H), 7.39-7.31 (m, 2H), 7.17 (s, 2H), 4.63 (d,J = 5.6 Hz, 2H) 1711

D^(f),  539, 571 14 473.0 (M⁺ + 1); 472.13 for C₂₄H₂₀N₆O₃S ¹H-NMR(DMSO-d₆, 400 MHz): δ 10.63 (s, 1H), 9.20 (t, J = 5.7 Hz, 1H), 8.79 (s,2H), 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.73-7.68 (m, 2H), 7.66-7.60 (m,2H), 7.42 (d, J = 8.4 Hz, 1H), 7.38-7.31 (m, 2H), 4.64 (d, J = 5.5 Hz,2H), 3.18 (s, 6H);   1714-A

D^(b),  539, 559 71 452.9 (M⁺ + 1); 452.09 for C₂₅H₁₆N₄O₃S ¹H-NMR(DMSO-d₆, 400 MHz): δ 10.64 (s, 1H), 9.26 (t, J = 5.6 Hz, 1H), 8.30 (s,1H), 8.21 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H),7.78 (dd, J = 7.7, 1.3 Hz, 1H), 7.71-7.61 (m, 4H), 7.43 (d, J = 8.4 Hz,1H), 7.38-7.32 (m, 2H), 4.69 (d, J = 5.8 Hz, 2H);   1736-A

D,  539, 560 49 472.0 (M⁺ + 1); 471.13 C₂₆H₂₁N₃O₄S ¹H-NMR (DMSO-d₆, 500MHz): δ 10.64 (s, 1H), 9.19 (t, J = 5.3 Hz, 1H), 7.78 (d, J = 7.2 Hz,1H), 7.73-7.60 (m, 6H), 7.42 (d, J = 8.1 Hz, 1H), 7.39-7.31 (m, 2H),7.01 (d, J = 8.4 Hz, 1H), 4.63 (d, J = 5.5 Hz, 2H), 3.83 (s, 3H), 2.19(s, 3H); 1737

E^(d),  539, 561 11 486.0 (M⁺ + 1); 467.11 for C₂₅H₁₇N₅O₃S ¹H-NMR(DMSO-d₆, 400 MHz): δ 13.26 (br s, 1H), 10.64 (br s, 1H), 9.22 (t, J =5.8 Hz, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 7.90 (dd, J = 8.7, 1.4 Hz, 1H),7.80-7.74 (m, 2H), 7.71 (s 1H), 7.67-7.58 (m, 3H), 7.43 (d, J = 8.4 Hz,1H), 7.39-7.30 (m, 2H), 4.66 (d, J = 5.6 Hz, 2H);   1738-A

D^(o),  539, 562 68 486.0 (M⁺ + 1); 485.14 for C₂₇H₂₃N₃O₄S ¹H-NMR(DMSO-d₆, 500 MHz): δ 10.64 (s, 1H), 9.21 (t, J = 5.8 Hz, 1H), 7.78 (dd,J = 7.7, 1.6 Hz, 1H), 7.73-7.69 (m, 2H), 7.66-7.60 (m, 2H), 7.56 (s,2H), 7.43 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.34 (t, J =7.5 Hz, 1H), 4.64 (d, J = 5.8 Hz, 2H), 3.68 (s, 3H), 2.26 (s, 6H); 1831

D^(o),  539, 564 16 479.1 (M⁺ + 1); 478.11 for C₂₇H₁₈N₄O₃S ¹H NMR((DMSO- d₆, 400 MHz): δ 10.65 (s, 1H), 9.27 (t, J = 5.8 Hz, 1H), 8.93(dd, J = 4.3, 1.8 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.50 (dd, J = 0.9,8.6 Hz, 1H), 8.29 (dd, J = 8.8, 2.1 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H),7.88 (s, 1H), 7.79 (dd, J = 7.7, 1.7 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H),7.68-7.56 (m, 3H), 7.44 (d, J = 8.4 Hz, 1H), 7.39-7.31 (m, 2H), 4.71 (d,J = 5.6 Hz, 2H) 1832

D^(o),  539, 565 10 479.1 (M⁺ + 1); 478.11 for C₂₇H₁₈N₄O₃S ¹H NMR((DMSO- d₆, 400 MHz): δ 10.65 (s, 1H), 9.34 (s, 1H), 9.29 (br t, J = 5.7Hz, 1H), 8.55 (d, J = 5.8 Hz, 1H), 8.51 (s, 1H), 8.21 (s, 2H), 7.95 (d,J = 5.6 Hz, 1H), 7.92 (s, 1H), 7.79 (dd, J = 7.7, 1.6 Hz, 1H), 7.72 (d,J = 2.0 Hz, 1H), 7.68-7.60 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.40-7.29(m, 2H), 4.72 (d, J = 5.5 Hz, 2H); 1861

D^(p),  539, 567 31 506.1 (M⁺ + 1); 505.08 for C₂₅H₁₉N₃O₅S₂ ¹H NMR((DMSO- d₆, 400 MHz): δ 10.63 (s, 1H), 9.25 (t, J = 5.8 Hz, 1H), 8.13(d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.89 (s, 1H), 7.77 (dd, J= 7.8, 1.4 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.61 (dd, J = 9.0, 2.0 Hz,2H), 7.42 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.32 (t, J =7.7 Hz, 1H), 4.68 (d, J = 5.5 Hz, 2H); 1862

D,  539, 576 15 507.1 (M⁺ + 1); 506.07 for C₂₄H₁₈N₄O₅S₂ ¹H NMR (DMSO-d₆,400 MHz): δ 10.64 (s, 1H), 9.26 (t, J = 5.7 Hz, 1H), 8.07 (d, J = 8.5Hz, 2H), 7.93-7.86 (m, 3H), 7.78 (dd, J = 7.7, 1.4 Hz, 1H), 7.70 (d, J =1.8 Hz, 1H), 7.67- 7.59 (m, 2H), 7.49- 7.40 (m, 3H), 7.39- 7.30 (m, 2H),4.69 (d, J = 5.6 Hz, 2H); 1863

D^(p),  539, 568 25 521.0 (M⁺ + 1); 520.09 for C₂₅H₂₀N₄O₅S₂ ¹H NMR (400MHz, DMSO-d₆) δ 10.63 (s, 1H), 10.05 (s, 1H), 9.20 (t, J = 5.8 Hz, 1H),7.83 (d, J = 8.8 Hz, 2H), 7.77 (dd, J = 7.7, 1.7 Hz, 1H), 7.73 (s, 1H),7.69 (d, J = 2.1 Hz, 1H), 7.65-7.60 (m Hz, 2H), 7.42 (d, J = 8.4 Hz,1H), 7.37- 7.30 (m, 2H), 7.26 (d, J = 8.8 Hz, 2H), 4.64 (d, J = 5.5 Hz,2H), 3.04 (s, 3H); 1865

G^(a),  539, 485 34 451.1 (M⁺ + 1); 450.14 for C₂₃H₂₂N₄O₄S ¹H NMR((DMSO- d₆, 400 MHz): δ 10.62 (s, 1H), 9.05- 8.93 (m, 1H), 7.78 (dd, J =7.7, 1.6 Hz, 1H), 7.71-7.55 (m, 3H), 7.44-7.28 (m, 3H), 6.99 (s, 1H),4.73 (d, J = 4.1 Hz, 1H), 4.41 (d, J = 5.5 Hz, 2H), 3.76-3.52 (m, 3H),3.14-3.05 (m, 2H), 1.82-1.70 (m, 2H), 1.46-1.33 (m, 2H); 1866

M^(a),  539, 545 14 485.1 (M⁺ + 1); 484.09 C₂₂H₂₀N₄O₅S₂ ¹H NMR (DMSO-d₆,400 MHz): δ 10.63 (s, 1H), 9.06 (t, J = 5.6 Hz, 1H), 7.78 (d, J = 6.7Hz, 1H), 7.69-7.58 (m, 3H), 7.41 (d, J = 8.3 Hz, 1H), 7.38-7.30 (m, 2H),7.07 (s, 1H), 4.44 (d, J = 5.5 Hz, 2H), 3.91-3.84 (m, 4H), 3.23-3.14 (m,4H); 1893

H,  539, 610 9 435.0 (M⁺ + 1); 434.05 C₂₁H₁₄N₄O₃S₂ ¹H NMR (DMSO-d₆, 400MHz): δ 10.63 (s, 1H), 9.25 (t, J = 5.5 Hz, 1H), 7.95 (d, J = 3.1 Hz,1H), 7.90 (d, J = 3.1 Hz, 1H), 7.86 (s, 1H), 7.78 (dd, J = 7.7, 1.6 Hz,1H), 7.69 (d, J = 2.0 Hz, 1H), 7.66-7.60 (m, 2H), 7.43 (d, J = 8.3 Hz,1H), 7.39- 7.31 (m, 2H), 4.67 (d, J = 5.5 Hz, 2H); D^(a): Pd(PPh₃)₄ (0.1equiv), reaction temp 90-100° C.; D^(b): Pd(PPh₃)₄ (0.1 equiv), Na₂CO₃(3.0 equiv); D^(c): Pd(PPh₃)₄ (0.1 equiv), boronic acid (2 equiv),Na₂CO₃ (5 equiv), reaction time 4 h; D^(d): Pd(PPh₃)₄ (0.1 equiv),reaction temp 110° C.; D^(e): 1,4-dioxane: H₂O (4:1); D^(f): Pd(PPh₃)₄(0.1 equiv), reaction performed in a sealed tube; D^(g): reactionperformed at 80° C.; D^(i): boronate ester (2 equiv); D^(j): Pd(PPh₃)₄(0.1 equiv), boronic acid (2.5 equiv), Na₂CO₃ (5 equiv), 80-90° C.;D^(l): Pd(PPh₃)₄ (0.1 equiv), boronic acid (2 equiv), Na₂CO₃ (5 equiv),reaction time 16 h; D^(O): Reaction performed in a sealed tube; D^(p):DME:H₂O (3:1), Na₂CO₃ (3 equiv), boronic acid/Ester (1.2 equiv),reaction performed in sealed tube, reaction temp 120° C., 16 h; D^(q):Reaction time 24 h; D^(r): Cs₂CO₃ (3 equiv), reaction performed insealed tube at 120° C., reaction time 16 h; D^(s): Na₂CO₃ (3.5 equiv),boronic acid (3 equiv), Pd(dppf)Cl₂ (0.1 equiv), DME, sealed tube, 120°C., 16 h; E^(b): boronate ester (2.5 equiv), reaction time 16 h at 120°C., sealed tube; E^(c): Pd(PPh₃)₄ (0.1 equiv), 100° C., reaction time 24h; E^(d): Pd(PPh₃)₄ (0.1 equiv), 120° C., reaction time 48 h; F^(a):Amine (3 equiv), 160° C., 16 h; G^(a): Amine (3 equiv), DIPEA (3 equiv),100° C., 20 h; G^(b): Amine (1.5 equiv), 110° C., 16 h; G^(C): Amine (2equiv), 160° C., 20 h; G^(d) Amine (2 equiv), DIPEA (3 equiv), 160° C.,16 h; H^(a): 700 mg of crude tin reagent was taken for the 200 mg batch;H^(b): 2 g of crude tin reagent was taken for the 200 mg batch,Pd(dppf)Cl₂ (0.1 equiv), 100° C., reaction time 16 h; H^(d): tin reagent(1 equiv), Pd(dppf)Cl₂ (0.1 equiv), 1,4-dioxane, 110° C., 16 h; H^(d):tin reagent (5 equiv), 120° C.; I^(a): amine (1.2 equiv), Cs₂CO₃ (3equiv); I^(b): Cs₂CO₃ (2 equiv); J^(a): amine (1.5 equiv), Xantphos(0.05 equiv), Pd₂(dba)₃ (0.025 equiv), Cs₂CO₃ (3.5 equiv) conventionalheating, 100-110° C.; 16 h; J^(b): Cs₂CO₃ (3 equiv), t-BuXphos (0.07equiv), Pd₂(dba)₃ (0.05 equiv), 1,4-dioxane, sealed tube, 100° C., 16 h;K^(a): amine (2 equiv), Cs₂CO₃ (5 equiv); NMP, sealed tube 120° C., 16h;

Synthesis of 1432 & 1433

Synthesis of 1-(thiazol-5-yl) ethan-1-one oxime (618)

To a stirring solution of compound 267 (800 mg, 6.29 mmol) in MeOH (20mL) under inert atmosphere was added hydroxyl amine hydrochloride (875mg, 12.59 mmol) and pyridine (2 mL) dropwise for 5 min at 0° C. warmedto RT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo dilutedwith water (50 mL) and stirred for 30 min. The precipitated solid wasfiltered dried in vacuo to afford compound 618 (800 mg, 90%) as whitesolid. TLC: 40% EtOAc/hexanes (R_(f): 0.4, 0.6); 41 NMR (DMSO-d₆, 400MHz) (Mixture of E/Z isomers): δ 11.86 (s, 1H), 11.41 (s, 0.6H), 9.19(s, 1H), 9.01 (s, 0.56H), 8.35 (s, 1H), 8.15 (s, 0.65H), 2.31 (s, 3H),2.21 (s, 2H).

Synthesis of 1-(thiazol-5-yl) ethan-1-amine (619)

To a stirring solution of compound 618 (800 mg, 5.63 mmol) inMeOH:acetic acid (1:1, 20 mL) under inert atmosphere were zinc powder(2.2 g, 33.80 mmol) at RT; heated at 50° C. and stirred for 4 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite washed with MeOH (3×10 mL).The filtrate was removed in vacuo, the residue was diluted with water(20 mL), basified with aqueous ammonia (15 mL) and extracted with EtOAc(3×50 mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude compound 619(racemic) (700 mg, 92%) as brown syrup. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4,0.6); ¹H NMR (DMSO-d₆, 400 MHz): δ 8.90 (s, 1H), 7.71 (s, 1H), 4.33-4.28(m, 1H), 3.38 (t, J=6.4 Hz, 1H), 1.87 (s, 3H).

Synthesis of 11-oxo-N-(1-(thiazol-5-yl) ethyl)-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-8-carboxamide (620 Racemic)

Using typical procedure A the title compound was prepared with DBT-Acid(150 mg, 0.55 mmol) and compound 619 racemic (109 mg, 0.66) to affordcompound 620 (Racemic) (100 mg, 48%); TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.5);¹H NMR (DMSO-d₆, 400 MHz): δ 10.87 (br s, 1H), 9.14 (d, J=8.0 Hz, 1H),8.95 (s, 1H), 7.79 (d, J=3.6 Hz, 2H), 7.70-7.58 (m, 3H), 7.56-7.42 (m,3H), 5.48-5.41 (m, 1H), 1.60 (s, 3H); LC-MS: 98.31%; 381.9 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.03 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):97.68%; (column; Eclipse XDB C-18 (150×4.6 mm, 5.0 μm); RT 7.58 min.ACN: 0.05% TFA (Aq); 1.0 mL/min) (IP14012554); Chiral HPLC: 35.10%,R_(t)=9.01 min (Chiralpak-IA, 250×4.6 mm, 5 μm); mobile phase (A) 0.1%DEA in n-Hexane (B) CH₂Cl₂:MeOH (50:50) (A:B:: 63:35); Flow Rate: 1.0mL/min).

The racemic compound 620 (100 mg) was separated by preparative HPLCusing a CHIRALPAK-IC column (250×20 mm×5 μm) (10 mg loading; mobilephase (A) 0.1% DEA in n-Hexane (B) CH₂Cl₂:MeOH:DMF (65:35:05) (A:B::75:25) to afford 1432 (10 mg) and 1433 (15 mg) as an off-white solids.

Analytical Data of 1432

TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H NMR (DMSO-d₆, 400 MHz): δ 10.75 (s,1H), 9.02 (d, J=7.8 Hz, 1H), 8.95 (s, 1H), 7.79 (s, 1H), 7.72-7.64 (m,3H), 7.62-7.58 (m, 1H), 7.56-7.41 (m, 3H), 5.45 (t, J=7.0 Hz, 1H), 1.57(d, J=6.8 Hz, 3H); LC-MS: 96.06%; 381.8 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.03 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 95.02%; (column;Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT 7.79 min. ACN: 0.05% TFA (Aq);1.0 mL/min) (IP15010530); Chiral HPLC: 96.24%, R_(t)=14.33 min(Chiralpak-IA, 250×4.6 mm, 5 μm); mobile phase (A) 0.1% DEA in n-Hexane(B) CH₂Cl₂:MeOH:DMF (65:35:05) (A:B: 75:25); Flow Rate: 1.0 mL/min).

Analytical Data of 1433

TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H NMR (DMSO-d₆, 400 MHz): δ 10.75 (s,1H), 9.03 (d, J=8.3 Hz, 1H), 8.95 (s, 1H), 7.79 (s, 1H), 7.71-7.63 (m,3H), 7.62-7.58 (m, 1H), 7.56-7.42 (m, 3H), 5.48-5.47 (m, 1H), 1.57 (d,J=6.9 Hz, 3H); LC-MS: 96.65%; 381.9 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 2.68 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.53%; (column; Zorbax SBC-18 (150×4.6 mm, 3.5 μm); RT 7.76 min. ACN: 0.05% TFA (Aq); 1.0 mL/min)(IP15010229). Chiral HPLC: 99.87%, R_(t)=16.90 min (Chiralpak-IA,250×4.6 mm, 5 μm); mobile phase (A) 0.1% DEA in n-Hexane (B)CH₂Cl₂:MeOH:DMF (65:35:05) (A:B: 75:25); Flow Rate: 1.0 mL/min).

Synthesis of 1602

Synthesis of methyl (5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) glycinate (622)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (500 mg, 2.01 mmol) in DMF (10 mL) were added methylglycinate hydrochloride 621 (506 mg, 4.03 mmol), potassium iodide (334mg, 2.01 mmol) and purged under argon atmosphere for 15 min in a sealedtube. To this were added and cesium carbonate (1.97 g, 6.04 mmol) purgedunder argon atmosphere for 5 min; followed by addition of Pd₂(dba)₃(92.3 mg, 0.10 mmol), ^(t)Bu-Me₄Xphos (96.9 mg, 0.20 mmol) at RT; heatedto 100° C. and stirred for 18 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture diluted withwater (100 mL) and extracted with EtOAc (2×100 mL). The combined organicextracts were washed with water (100 mL) and brine (50 mL), dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using40% EtOAc/hexanes further purified by preparative HPLC purification toafford compound 622 (210 mg, 9%) as an off-white solid. TLC: 30%EtOAc/hexanes (R_(f): 0.5); ¹H-NMR (DMSO-d₆, 500 MHz): 7.81 (t, J=5.2Hz, 1H), 7.28 (t, J=5.5 Hz, 1H), 6.75 (s, 1H), 4.04 (d, J=5.5 Hz, 2H),3.99 (d, J=6.1 Hz, 2H), 3.62 (s, 3H), 1.38 (s, 9H).

Synthesis of methyl (5-(aminomethyl) thiazol-2-yl) glycinatehydrochloride (623)

To a stirring solution of compound 622 (200 mg, 0.66 mmol) in CH₂Cl₂ (5mL) was added 4 N HCl in 1, 4-dioxane (5 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was triturated with diethyl ether (2×5 mL) and dried invacuo to afford compound 623 (190 mg, HCl salt) as an off-white solid.TLC: 40% EtOAc/hexanes (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.69(br s, 1H), 8.23 (br s, 3H), 7.15 (s, 1H), 4.14-4.11 (m, 2H), 4.05 (q,J=5.4 Hz, 2H), 3.64 (s, 3H).

Synthesis of methyl (5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamido) methyl) thiazol-2-yl) glycinate (624)

To a stirring solution of compound 6 (100 mg, 0.49 mmol) in DMF (5 mL)under inert atmosphere were added compound 623 (90 mg, 0.37 mmol),EDCI.HCl (137 mg, 0.75 mmol), HOBt (102 mg, 0.75 mmol) anddiisopropylethylamine (0.35 mL, 1.89 mmol) at 0° C.; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with ice-cold water (50mL). The obtained solid was filtered and dried in vacuo to obtain thecrude. The crude was purified through silicagel column chromatographyusing 4-10% MeOH/CH₂Cl₂ to afford compound 624 (95 mg, 57%) as paleyellow solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆ 500MHz): δ 10.75 (s, 1H), 9.03 (t, J=6.1 Hz, 1H), 7.83 (t, J=6.2 Hz, 1H),7.72-7.63 (m, 3H), 7.59-7.42 (m, 4H), 6.86 (s, 1H), 4.37 (d, J=5.8 Hz,2H), 3.99 (d, J=6.1 Hz, 2H), 3.61 (s, 3H).

Synthesis of (5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamido) methyl) thiazol-2-yl) glycine (1602)

To a stirring solution of compound 624 (90 mg, 0.19 mmol) in THF:H₂O(1:1, 10 mL) was added lithium hydroxide monohydrate (46 mg, 0.99 mmol)at RT and stirred for 4 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(50 mL), washed with EtOAc (2×10 mL). The pH of the aqueous layer wasacidified with 4 N HCl to ˜2. The precipitated solid was filtered,washed with water (10 mL) and triturated with CH₃CN (5 mL) and dried invacuo to afford 1602 (60 mg, 69%) as an off-white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ 10.75 (s, 1H),9.02 (t, J=5.5 Hz, 1H), 7.71-7.62 (m, 3H), 7.60-7.43 (m, 5H), 6.85 (s,1H), 4.37 (d, J=5.5 Hz, 2H), 3.76 (d, J=4.3 Hz, 2H); LC-MS: 93.40%;440.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT1.77 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);HPLC (purity): 94.16%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm);RT 5.80 min. 0.05% TFA (Aq): ACN; 1.0 mL/min).

Synthesis of 1603

Synthesis of methyl 2-((5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) thio) acetate (626)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (1 g, 4.03 mmol) in 1, 4-dioxane (10 mL) was added methylthioglycolate 625 (1.3 mL, 12.09 mmol), potassium iodide (1.34 g, 8.06mmol) and cesium carbonate (2.62 g, 8.06 mmol) at RT in a sealed tubeand purged under argon atmosphere for 15 min. To this were addedPd₂(dba)₃ (184 mg, 0.20 mmol), Xantphos (163 mg, 0.28 mmol) at RT;heated to 120° C. and stirred for 18 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The residue was diluted with EtOAc (200 mL), washed with water(100 mL) and brine (50 mL). The organic extract was dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 20-30%EtOAc/hexanes to afford compound 626 (620 mg, 48%) as pale yellow thicksyrup. TLC: 30% EtOAc/hexanes (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ7.49 (t, J=6.1 Hz, 1H), 7.47 (s, 1H), 4.22 (d, J=5.8 Hz, 2H), 4.12 (s,2H), 3.65 (s, 3H), 1.38 (s, 9H).

Synthesis of methyl 2-((5-(aminomethyl) thiazol-2-yl) thio) acetatehydrochloride (627)

To a stirring solution of compound 626 (500 mg, 1.57 mmol) in CH₂Cl₂ (2mL) was added 4 N HCl in 1, 4-dioxane (5 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was triturated with diethyl ether (2×5 mL) and dried invacuo to afford compound 627 (400 mg, HCl salt) as an off-white solid.TLC: 30% EtOAc/hexanes (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.47(br s, 3H), 7.75 (s, 1H), 4.24 (q, J=5.7 Hz, 2H), 4.18 (s, 2H), 3.66 (s,3H).

Synthesis of methyl 2-((5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamido) methyl) thiazol-2-yl) thio) acetate (628)

To a stirring solution of compound 6 (150 mg, 0.58 mmol) in DMF (5 mL)under inert atmosphere were added compound 627 (139 mg, 0.64 mmol),EDCI.HCl (224 mg, 1.17 mmol), HOBt (158 mg, 1.17 mmol) anddiisopropylethylamine (0.30 mL, 1.76 mmol) at 0° C.; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with water (50 mL), theprecipitated solid was filtered and dried in vacuo to afford compound628 (180 mg, 65%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f):0.4); ¹H-NMR (DMSO-d₆ 500 MHz): δ 10.75 (br s, 1H), 9.20 (t, J=4.6 Hz,1H), 7.71-7.62 (m, 3H), 7.59-7.40 (m, 5H), 4.53 (d, J=5.2 Hz, 2H), 4.10(s, 2H), 3.62 (s, 3H).

Synthesis of 2-((5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamido) methyl) thiazol-2-yl) thio) acetic acid (1603)

To a stirring solution of compound 628 (100 mg, 0.21 mmol) in THF:H₂O(5:1, 6 mL) was added lithium hydroxide monohydrate (15 mg, 0.31 mmol)at 0° C.; warmed to RT and stirred for 2 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasvolatiles were removed in vacuo. The crude was diluted with water (20mL) and washed with EtOAc (2×10 mL). The pH of the aqueous layer wasadjusted with 4 N HCl to ˜2. The precipitated solid was filtered anddried in vacuo to afford 1603 (42 mg, 43%) as an off-white solid. TLC:10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ 10.76 (s,1H), 9.21 (t, J=5.8 Hz, 1H), 7.71-7.64 (m, 3H), 7.61-7.42 (m, 5H), 4.54(d, J=4.9 Hz, 2H), 3.99 (s, 2H); LC-MS: 95.88%; 457.9 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.11 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 92.76%;(column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 7.99 min. ACN+0.5%TFA (Aq)+0.5% TFA (Aq)+5% ACN; 1.0 mL/min).

Synthesis of 1735

Synthesis of di-tert-butyl ([2, 2′-bithiazole]-5, 5′-diylbis(methylene)) dicarbamate (631)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (2 g, 8.06 mmol) in Toluene:EtOH:H₂O (2:2:1, 25 mL) underinert atmosphere was sodium carbonate (1.70 g, 16.12 mmol) at RT andpurged under argon atmosphere for 30 min; added Pd(dppf)Cl₂ (589 mg,0.80 mmol) and heated to 100° C. and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas filtered through celite. The filtrate was concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 25% EtOAc/hexanes to afford compound 631 (650 mg)as an off-white solid. TLC: 40% EtOAc/hexanes (R_(f): 0.3); ¹H-NMR(DMSO-d₆, 500 MHz): δ 7.74 (s, 2H), 7.60 (br s, 2H), 4.34 (d, J=6.1 Hz,4H), 1.40 (s, 18H); LC-MS: 80.62%; 427.0 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.56 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of [2, 2′-bithiazole]-5, 5′-diyldimethanamine dihydrochloride(632)

To a stirring solution of compound 631 (650 mg, 0.52 mmol) in CH₂Cl₂ (15mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (1 mL) at0° C.; warmed to RT and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was titurated with CH₂Cl₂ (2×5 mL)and dried in vacuo to afford compound 632 (380 mg, 84%; HCl salt) aswhite solid. TLC: 40% EtOAc/hexanes (R_(f): 0.1); LC-MS: 99.31%; 227.2(M⁺+1); (column; Atlantis T3 (150×4.6 mm, 3 μm); RT 5.96 min. 2.5 mM Aq.NH₄OAc:ACN; 1.0 mL/min).

Synthesis of 2, 5-dioxopyrrolidin-1-yl 11-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-8-carboxylate (630)

To a stirring solution of 6 (1 g, 3.69 mmol) in THF (20 mL) under inertatmosphere were added diisopropylethylamine (1.98 mL, 11.07 mmol), CDI(910 mg, 4.42 mmol) and N-hydroxysuccinimide 629 (509 mg, 4.42 mmol) at0° C.; warmed to RT and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was filteredthrough celite. The filtrate was diluted with EtOAc (2×50 mL) washedwith water (50 mL). The organic extract was dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude, which wastiturated with 10% diethylether/pentane (10 mL) and dried in vacuo toafford compound 630 (1 g, 74%) as an white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.8); ¹H NMR (DMSO-d₆, 500 MHz): δ 10.89 (s, 1H), 7.91 (s, 1H),7.85-7.80 (m, 2H), 7.71 (dd, J=7.5, 1.2 Hz, 1H), 7.60-7.47 (m, 3H), 2.88(s, 4H); LC-MS: 96.35%; 368.9 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 2.25 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min).

Synthesis of N-((5′-(aminomethyl)-[2, 2′-bithiazol]-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide (633)

To a stirring solution of compound 630 (365 mg, 1.22 mmol) in DMF (15mL) under inert atmosphere was added diisopropylethylamine (0.43 mL,2.43 mmol) at 0° C. stirred for 10 min; added compound 632 (300 mg, 0.81mmol), heated to 50° C. and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasdiluted with ice-cold water (100 mL) and extracted with 10% MeOH/CH₂Cl₂(2×50 mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude with tituratedwith CH₂Cl₂ (20 mL) and dried in vacuo to afford crude compound 633 (250mg) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); LC-MS:40.20%; 480.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.80 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of N-((5′-(aminomethyl)-[2,2′-bithiazol]-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide hydrochloride (1735)

To a stirring solution of compound 633 (250 mg, 0.52 mmol) in CH₂Cl₂ (15mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (0.4 mL) at0° C.; warmed to RT and stirred for 1 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was triturated with CH₂Cl₂ (10 mL),MeOH (5 mL) and further purified by preparative HPLC purification toafford 1735 (28 mg, 4%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(eluted 2 times) (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 500 MHz): δ 10.79 (s,1H), 9.33 (t, J=5.8 Hz, 1H), 8.25 (br s, 3H), 7.97 (s, 1H), 7.88 (s,1H), 7.72-7.67 (m, 3H), 7.60 (dd, J=8.4, 2.0 Hz, 1H), 7.56-7.44 (m, 3H),4.67 (d, J=5.8 Hz, 2H), 4.37 (s, 2H); LC-MS: 99.23%; 480.0 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.77 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):96.62%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 5.52 min.ACN+5% 0.05% TFA (Aq): 0.5% TFA (Aq)+5% ACN; 1.0 mL/min, Diluent:DMSO:ACN:water).

Synthesis of 1599-A & 1599

Synthesis of methyl 4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) benzoate (635)

To a stirring solution of tert-butyl ((2-chlorothiazol-5-yl) methyl)carbamate 224 (500 mg, 2.01 mmol) in 2-methyltetrahydrofuran (10 mL)under argon atmosphere were added (4-(methoxycarbonyl) phenyl) boronicacid 634 (435 mg, 2.41 mmol), sodium carbonate (427 mg, 4.02 mmol) at RTin a sealed tube and purged under argon atmosphere for 10 min. To thiswas added Pd(dppf)Cl₂ (73.7 mg, 0.10 mmol); heated to 100° C. andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with EtOAc (100 mL),washed with water (50 mL). The organic extract was dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through mobile phase liquid chromatography using 10%EtOAc/hexanes to afford compound 635 (280 mg, 40%) as pale yellow solid.TLC: 30% EtOAc/hexanes (R_(f): 0.3); ¹H-NMR (DMSO-d₆, 500 MHz): δ8.05-8.02 (m, 4H), 7.76 (s, 1H), 7.58 (t, J=5.6 Hz, 1H), 4.35 (d, J=6.1Hz, 2H), 3.86 (s, 3H), 1.39 (s, 9H).

Synthesis of methyl 4-(5-(aminomethyl) thiazol-2-yl) benzoatehydrochloride (636)

To a stirring solution of compound 635 (280 mg, 0.80 mmol) in CH₂Cl₂ (10mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (10 mL) at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was washed with diethyl ether (2×30mL) and dried in vacuo to afford compound 636 (200 mg, 88%) as palebrown solid. TLC: 30% EtOAc/hexanes (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500MHz): δ 8.57 (br s, 3H), 8.10-8.09 (m, 4H), 8.06 (s, 1H), 4.38 (d, J=4.0Hz, 2H), 3.89 (s, 3H).

Synthesis of methyl 4-(5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamido) methyl) thiazol-2-yl) benzoate (1599-A)

To a stirring solution of compound 636 (200 mg, 0.74 mmol) in DMF (8 mL)under inert atmosphere were added EDCI.HCl (211 mg, 1.10 mmol), HOBt(149 mg, 1.10 mmol), compound 248 (250 mg, 0.88 mmol) anddiisopropylethylamine (0.70 mL, 3.69 mmol) at 0° C.; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was poured into ice-cold water (50mL) and stirred for 10 min. The precipitated solid was filtered anddried in vacuo to obtain the crude. The crude was washed with diethylether (2×10 mL), n-pentane (2×10 mL) and dried in vacuo to affordcompound 1599-A (140 mg, 38%) as an off-white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H NMR (DMSO-d₆, 400 MHz): δ 10.78 (s, 1H),9.31 (t, J=5.5 Hz, 1H), 8.03 (s, 4H), 7.87 (s, 1H), 7.74-7.66 (m, 3H),7.63-7.59 (m, 1H), 7.57-7.41 (m, 3H), 4.68 (d, J=5.5 Hz, 2H), 3.87 (s,3H); LC-MS: 94.78%; 502.3 (M⁺+1); (column; X-select CSH C-18 (50×3.0 mm,2.5 μm); RT 3.95 min. 2.5 mM Aq NH₄OAc:ACN; 0.8 mL/min). HPLC (purity):91.89%; (column; Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT 9.46 min. ACN:0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN:water).

Synthesis of 4-(5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamido) methyl) thiazol-2-yl) benzoic acid (1599)

To a stirring solution of 1599-A (100 mg, 0.419 mmol) in THF:H₂O (4:1, 5mL) was added lithium hydroxide monohydrate (21 mg, 0.49 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with ice-cold water (10mL) and the pH was adjusted to 2 N with 2 N HCl to ˜4. The precipitatedsolid was filtered washed with water (50 mL) 20% EtOAc/hexanes (5 mL),diethyl ether (5 mL), n-pentane (10 mL) and dried in vacuo to afford1599 (70 mg, 72%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f).0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 13.10 (br s, 1H), 10.79 (s, 1H), 9.31(t, J=5.7 Hz, 1H), 8.04-7.96 (m, 4H), 7.86 (s, 1H), 7.75-7.64 (m, 3H),7.61 (dd, J=8.0, 1.7 Hz, 1H), 7.57-7.42 (m, 3H), 4.68 (d, J=5.6 Hz, 2H).LC-MS: 92.86%; 488.3 (M⁺+1); (column; X-select CSH C-18 (50×3.0 mm, 2.5μm); RT 2.93 min. 2.5 mM Aq NH₄OAc:ACN; 0.8 mL/min). HPLC (purity):95.00%; (column; Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT 7.21 min.ACN+5% 5 mM Aq NH₄OAc: 5 mM Aq NH₄OAc+5% ACN; 0.8 mL/min), Diluent:ACN:water).

Synthesis of 1607

Synthesis of ethyl 2-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenoxy) acetate (638)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (250 mg, 0.81 mmol) and ethyl 2-bromoacetate 637(204 mg, 1.22 mmol) in acetone (15 mL) under inert atmosphere was addedpotassium carbonate (338 mg, 2.45 mmol) at RT; heated to 70° C. andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the volatiles were removed in vacuo. The residue wasdiluted with water (100 mL) and extracted with EtOAc (2×150 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 20% EtOAc/hexanes toafford compound 638 (250 mg, 78%) as an off-white solid. TLC: 20%EtOAc/hexanes (R_(f). 0.5); ¹H NMR (DMSO-d₆, 500 MHz): δ 7.82 (d, J=8.7Hz, 2H), 7.62 (s, 1H), 7.53 (t, J=5.5 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H),4.85 (s, 2H), 4.31 (d, J=5.8 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 1.40 (s,9H), 1.22 (t, J=7.1 Hz, 3H).

Synthesis of ethyl 2-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) acetatehydrochloride (639)

To a stirring solution of compound 638 (250 mg, 0.63 mmol) in CH₂Cl₂ (10mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (10 mL) at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was washed with diethyl ether (10mL) and dried in vacuo to afford compound 639 (190 mg, 90%) as whitesolid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ8.55 (br s, 3H), 7.90 (s, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.04 (d, J=8.7Hz, 2H), 4.85 (s, 2H), 4.30 (q, J=5.4 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H),1.20 (t, J=7.1 Hz, 3H).

Synthesis of ethyl 2-(4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo[b, f] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy)acetate (640)

To a stirring solution of compound 6 (75 mg, 0.27 mmol) in DMF (5 mL)under inert atmosphere were added compound 639 (100 mg, 0.30 mmol),EDCI.HCl (80 mg, 0.41 mmol), HOBt (56 mg, 0.41 mmol), anddiisopropylethylamine (0.27 mL, 1.47 mmol) at 0° C.; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was poured into ice-cold water (50mL) and extracted with EtOAc (2×150 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 3% MeOH/CH₂Cl₂ to afford compound 640 (80 mg, 53%)as white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (DMSO-d₆, 500MHz): δ 10.77 (s, 1H), 9.25 (t, J=4.9 Hz, 1H), 7.80 (d, J=8.4 Hz, 2H),7.74-7.65 (m, 4H), 7.60 (d, J=7.8 Hz, 1H), 7.56-7.43 (m, 3H), 7.01 (d,J=8.4 Hz, 2H), 4.84 (s, 2H), 4.64 (d, J=5.2 Hz, 2H), 4.17 (q, J=6.8 Hz,2H), 1.21 (t, J=6.9 Hz, 3H).

Synthesis of 2-(4-(5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) acetic acid(1607)

To a stirring solution of compound 640 (80 mg, 0.15 mmol) in THF:H₂O(4:1, 10 mL) was added lithium hydroxide monohydrate (32 mg, 0.77 mmol)at RT and stirred for 2 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. Theresidue was diluted water (50 mL) and the pH was acidified with 2 N HClto ˜6. The precipitated solid was filtered and dried in vacuo to afford1607 (70 mg, 80%) as white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f) 0.2);¹H-NMR (DMSO-d₆, 500 MHz): δ 13.06 (br s, 1H), 10.77 (s, 1H), 9.25 (t,J=5.6 Hz, 1H), 7.80 (d, J=9.0 Hz, 2H), 7.72-7.65 (m, 4H), 7.62-7.59 (m,1H), 7.55-7.43 (m, 3H), 6.99 (d, J=9.0 Hz, 2H), 4.73 (s, 2H), 4.63 (d,J=5.5 Hz, 2H); LC-MS: 96.16%; 517.9 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 2.17 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.19%; (column; Zorbax SBC-18 (150×4.6 mm, 3.5 μm); RT 7.98 min; 0.05% TFA (Aq): 5% ACN; 1.0mL/min, Diluent: ACN:water).

Synthesis of 1909

Synthesis of 11-oxo-N-((2-(3-oxoazepan-1-yl) thiazol-5-yl) methyl)-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(1909)

To a stirring solution of 1908 (100 mg, 0.19 mmol) in DMSO (10 mL) underinert atmosphere was added iodoxybenzoic acid (218 mg, 0.97 mmol) at RTand stirred for 24 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted withice-cold water (50 mL) and extracted with 10% MeOH/CH₂Cl₂ (2×50 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 5% MeOH/CH₂Cl₂ to afford1909 (60 mg, 60%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f):0.5); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.50 (s, 1H), 9.29 (t, J=5.7 Hz,1H), 8.04 (d, J=8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.77 (m, 4H), 7.03(s, 1H), 4.45 (d, J=5.6 Hz, 2H), 4.15 (s, 2H), 3.66-3.59 (m, 2H),2.28-2.23 (m, 2H), 1.86-1.64 (m, 4H); LC-MS: 91.22%; 511.1 (M⁺+1);(column; Ascentis Express C-18, (50×3.0 mm, 2.7 μm); RT 1.93 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):91.03%; (column; X-select CSH-C18 (150×4.6 mm, 3.5 μm); RT 9.10 min. 5mM NH₄OAc: ACN; 1.0 mL/min, Diluent: DMSO:ACN:water).

Synthesis of 1822

Synthesis of N-((2-(3-methoxybenzyl) thiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(1822)

To a stirring solution N-((2-(3-methoxybenzyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1822-A) (150 mg, 0.28 mmol) inCH₂Cl₂ (15 mL) under inert atmosphere was added BBr₃ (0.082 mL, 0.86mmol) at 0° C.; warmed to RT and stirred for 8 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas quenched with ice-cold water (10 mL) and extracted with 10%MeOH/CH₂Cl₂ (50 mL). The precipitated solid was filtered, and washedwith 10% NaHCO₃ solution (20 mL). The organic extract was dried oversodium sulfate and concentrated in vacuo to obtain the crude. The crudewas purified through silicagel column chromatography using 4%MeOH/CH₂Cl₂, and further purified by second column chromatography using8% isopropanol/CH₂Cl₂ to afford 1822 (50 mg, 34%) as an off-white solid.TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 500 MHz): δ 11.47(s, 1H), 9.34 (t, J=5.8 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.97 (br t,J=8.1 Hz, 2H), 7.92-7.82 (m, 2H), 7.81 (s, 1H), 7.76 (br d, J=8.1 Hz,1H), 7.55 (s, 1H), 7.08 (br d, J=8.1 Hz, 2H), 6.69 (br d, J=8.1 Hz, 2H),4.55 (d, J=5.2 Hz, 2H), 4.10 (s, 2H); LC-MS: 93.47%; 506.1 (M+1)⁺column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.01 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):93.81%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 7.53 min.0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent:DMSO:ACN:water).

Synthesis of 1823

Synthesis of N-((2-(4-hydroxybenzyl) thiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(1823)

To a stirring solution of N-((2-(4-methoxybenzyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, 1] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1823-A) (80 mg, 0.15 mmol) inCH₂Cl₂ (6 mL) under inert atmosphere was added BBr₃ (0.029 mL, 0.30mmol) at 0° C.; warmed to RT and stirred for 24 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas quenched with ice-cold water (10 mL) and the precipitated solid wasfiltered, and washed with 10% NaHCO₃ solution (20 mL). This wastiturated with 30% isopropanol/EtOAc (30 mL) to afford 1823 (68 mg, 87%)as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR(DMSO-d₆, 500 MHz): δ 11.47 (s, 1H), 9.34 (t, J=5.8 Hz, 1H), 8.03 (d,J=8.1 Hz, 1H), 7.97 (br t, J=8.1 Hz, 2H), 7.92-7.82 (m, 2H), 7.81 (s,1H), 7.76 (br d, J=8.1 Hz, 1H), 7.55 (s, 1H), 7.08 (br d, J=8.1 Hz, 2H),6.69 (br d, J=8.1 Hz, 2H), 4.55 (d, J=5.2 Hz, 2H), 4.10 (s, 2H); LC-MS:93.47%; 506.1 (M+1)⁺ column; Ascentis Express C18, (50×3.0 mm, 2.7 μm);RT 2.01 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);HPLC (purity): 93.81%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm);RT 7.53 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent:DMSO:ACN:water).

Synthesis of 1653

Synthesis of N-((2-(4-carbamimidoylphenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1653)

To a stirring solution of N-((2-(4-cyanophenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide 1654-A (175 mg, 0.35 mmol) in dryTHF (5 mL) under inert atmosphere was added LiHMDS (1 M solution in THF,3.5 mL) at 0° C.; warmed to RT and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas quenched with ice-cold water (10 mL), diluted with EtOAc (10 mL).The precipitated solid was filtered and dried in vacuo to obtain thecrude. The crude was purified using preparative HPLC to afford 1653 (30mg, 16%) as white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.54 (s, 1H), 9.54 (t, J=5.7 Hz, 1H), 9.37 (s,2H), 9.00 (br s, 2H), 8.12 (d, J=8.5 Hz, 2H), 8.07 (d, J=8.3 Hz, 1H),8.01-7.96 (m, 2H), 7.93-7.86 (m, 5H), 7.84 (td, J=7.9, 1.3 Hz, 2H), 4.72(d, J=5.6 Hz, 2H); LC-MS: 94.34%; 518.1 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.75 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 90.29%; (column;Zorbax SB-C-18 (150×4.6 mm, 3.5 μm); RT 5.56 min. ACN+5% 0.05% TFA (Aq):0.05% TFA (Aq)+5% ACN; 1.0 mL/min, Diluent: ACN:water).

Synthesis of 1677-B

Synthesis of N-((2-(3-carbamoylphenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(1677-B)

To a stirring solution of N-((2-(3-cyanophenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, 1] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide 1677-A (226 mg, 0.45 mmol) in dryTHF (8 mL) under inert atmosphere was added LiHMDS (1 M solution in THF,4.5 mL) at 0° C.; warmed to RT and stirred for 18 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas quenched with ice-cold water (10 mL) and stirred for 30 min. Theprecipitated solid was filtered, washed with water and dried in vacuo toafford 1677-B (30 mg, 13%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.40 (br s, 1H), 9.50 (br t,J=4.8 Hz, 1H), 8.34 (s, 1H), 8.16 (br s, 1H), 8.04 (br t, J=7.6 Hz, 2H),8.00-7.78 (m, 8H), 7.56 (br t, J=7.7 Hz, 1H), 7.47 (br s, 1H), 4.71 (brd, J=5.3 Hz, 2H); LC-MS: 98.51%; 518.9 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 nm); RT 1.97 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.86%; (column; X-SelectCSH C-18 (150×4.6 mm, 3.5 nm); RT 7.12 min. ACN+5% 0.05% TFA (Aq): 0.05%TFA (Aq)+5% ACN; 1.0 mL/min, Diluent: DMSO:ACN:water).

Synthesis of 1901-B

Synthesis of N-((2-(4-cyanophenyl) thiazol-5-yl)methyl)-7-hydroxy-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1901-B)

To a stirring solution of N-((2-(4-cyanophenyl) thiazol-5-yl)methyl)-7-methoxy-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1901-A) (150 mg, 0.28 mmol) inCH₂Cl₂ (10 mL) under inert atmosphere was added BBr₃ (0.13 mL, 1.41mmol) at 0° C.; warmed to RT and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas quenched with ice-cold water (10 mL) and extracted with 10%MeOH/CH₂Cl₂ (2×50 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using 2%MeOH/CH₂Cl₂ and triturated EtOAc (5 mL), dried in vacuo to afford 1901-B(120 mg, 82%) as white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.82 (br s, 1H), 11.09 (s, 1H), 9.56 (br s, 1H),8.06 (d, J=8.3 Hz, 2H), 7.97-7.85 (m, 6H), 7.84-7.76 (m, 2H), 7.44 (s,1H), 4.74 (d, J=4.4 Hz, 2H); LC-MS: 97.63%; 517.0 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.32 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.29%;(column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 9.48 min. ACN+5%0.05% TFA 0.05% TFA+5% ACN; 1.0 mL/min, Diluent: DMSO:ACN:water)

Synthesis of 1970

Synthesis of N-((2-(4-carbamoyl-2-fluorophenyl)thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1970)

To a stirring solution of 1814 (100 mg, 0.19 mmol) in DMSO (5 mL) wereadded 30% H₂O₂ (2 mL, 20 vol) and potassium carbonate (267 mg, 1.93mmol) at 0° C.; warmed to RT and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturediluted with water (30 mL) and stirred for 1 h. The precipitated solidwas filtered, dried in vacuo to obtain the crude, which was trituratedwith EtOAc (2×20 mL) and dried in vacuo to afford 1970 (80 mg, 78%) asan off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆,400 MHz): δ 11.50 (br s, 1H), 9.51 (br t, J=5.4 Hz, 1H), 8.25 (br t,J=8.0 Hz, 1H), 8.13 (br s, 1H), 8.06 (br d, J=8.3 Hz, 1H), 8.01-7.94 (m,3H), 7.93-7.79 (m, 6H), 7.61 (br s, 1H), 4.74 (br d, J=5.1 Hz, 2H);LC-MS: 98.08%; 537.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 1.98 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 96.22%; (column; X-select CSH C-18 (150×4.6 mm,3.5 μm); RT 7.37 min. 0.05% TFA+5% ACN: ACN+0.05% TFA+5%; 1.0 mL/min;Diluent: DMSO:ACN:water).

Synthesis of 1952

Synthesis of N-((2-(4-(1H-pyrazol-1-yl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1952)

To a stirring solution of N-((2-(4-bromophenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, 1] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide 538 (100 mg, 0.18 mmol) inN-methyl-2-pyrrolidone (4 mL) under inert atmosphere were added1H-pyrazole 441 (24 mg, 0.35 mmol) and potassium phosphate tribasic (115mg, 0.54 mmol), copper(I) iodide (17 mg, 0.09 mmol) in a sealed tube atRT and purged under argon atmosphere for 15 min; heated to 150° C. andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was filtered through celite. Thefiltrate was concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 3-5% MeOH/CH₂Cl₂and triturated with diethylether (5 mL) to afford 1952 (30 mg, 31%) asan off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H-NMR (DMSO-d₆,500 MHz): δ 11.52 (br s, 1H), 9.49 (t, J=5.5 Hz, 1H), 8.58 (d, J=2.3 Hz,1H), 8.10-7.94 (m, 7H), 7.93-7.76 (m, 6H), 6.58 (s, 1H), 4.70 (d, J=5.2Hz, 2H); LC-MS: 95.99%; 542.0 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 2.31 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min); HPLC (purity): 92.85%; (Column; X-select CSH C-18(150×4.6 mm, 3.5 μm); RT 10.00 min. 5 mM NH₄OAc: ACN; 1.0 mL/min,Diluent: DMSO:ACN:water).

Synthesis of 1806

Synthesis of N-((2-(4-hydroxy-3, 5-dimethylphenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1806)

To a stirring solution of N-((2-(4-methoxy-3, 5-dimethylphenyl)thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5,5-dioxide (1806-A) (60 mg, 0.11 mmol) inCH₂Cl₂ (10 mL) was added BBr₃ (0.03 mL, 0.33 mmol) at 0° C.; warmed toRT and stirred for 24 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withice-cold water (10 mL) the precipitated solid was filtered and dried invacuo to obtain the crude which was titurated with MeOH (2 mL) and driedin vacuo to afford 1806 (30 mg, 52%) as an off-white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.52 (s, 1H),9.43 (t, J=5.5 Hz, 1H), 8.75 (br s, 1H), 8.05 (d, J=8.3 Hz, 1H),8.01-7.95 (m, 2H), 7.93-7.79 (m, 4H), 7.66 (s, 1H), 7.45 (s, 2H), 4.64(d, J=5.4 Hz, 2H), 2.19 (s, 6H); LC-MS: 97.68%; 520.0 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.24 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.67%;(column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 8.43 min. 5% 0.05%TFA+5% ACN: ACN+5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: DMSO:ACN:water).

Synthesis of 1804

Synthesis of N-((2-(4-hydroxy-3-methylphenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1804)

To a stirring solution of N-((2-(4-methoxy-3-methylphenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1804-A) (80 mg, 0.15 mmol) inCH₂Cl₂ (10 mL) was added BBr₃ (0.07 mL, 0.77 mmol) at 0° C.; warmed toRT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withice-cold water (10 mL). The aqueous layer was basified with saturatedsodium bicarbonate solution (10 mL) and the precipitated solid wasfiltered washed with diethyl ether (2×10 mL) and dried in vacuo toafford 1804 (40 mg, 52%) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂(R_(f): 0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.85 (s, 1H),9.43 (t, J=5.7 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 8.01-7.95 (m, 2H),7.92-7.79 (m, 4H), 7.66 (s, 1H), 7.59 (s, 1H), 7.53 (dd, J=8.3, 2.1 Hz,1H), 6.83 (d, J=8.4 Hz, 1H), 4.64 (d, J=5.6 Hz, 2H), 2.15 (s, 3H);LC-MS: 99.14%; 506.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 2.15 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 99.24%; (column; X-select CSH C-18 (150×4.6 mm,3.5 μm); RT 8.13 min. 5% 0.05% TFA+5% ACN: ACN+5% 0.05% TFA (Aq); 1.0mL/min, Diluent: DMSO:ACN:water).

Synthesis of 1879

Synthesis of N-((2-(5-hydroxypyridin-2-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1879)

To a stirring solution of 1879-A (50 mg, 0.098 mmol) in CH₂Cl₂ (5 mL)was under inert atmosphere was added BBr₃ (1 mL) at 0° C.; warmed to RTand stirred for 120 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withice-cold water (10 mL). The volatiles were concentrated in vacuo. The pHof the residue was adjusted to ˜7.0 with saturated NaHCO₃ solution (20mL). The precipitated solid was filtered and dried in vacuo to obtainthe crude. The crude was purified through silicagel columnchromatography using 3-5% MeOH/CH₂Cl₂ to afford compound 1879 (20 mg,42%) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR(DMSO-d₆, 500 MHz): δ 10.64 (s, 1H), 9.84 (s, 1H), 9.17 (t, J=5.2 Hz,1H), 7.78 (d, J=6.9 Hz, 1H), 7.72-7.58 (m, 5H), 7.53 (d, J=8.2 Hz, 1H),7.42 (d, J=8.3 Hz, 1H), 7.38-7.31 (m, 2H), 6.83 (d, J=8.3 Hz, 1H), 4.62(d, J=5.1 Hz, 2H), 2.15 (s, 3H); LC-MS: 95.08%; 457.9 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.19 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.99%;(column; Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT 7.56 min. ACN+5% 0.05%TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0 mL/min, Diluent: DMSO:ACN:water).

Synthesis of 1671

Synthesis of N-((2-(2-hydroxypyrimidin-5-yl)thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1671)

To a stirring solution of N-((2-(2-methoxypyrimidin-5-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1671-A) (80 mg, 0.15 mmol) inCH₂Cl₂ (10 mL) was added BBr₃ (0.14 mL, 0.78 mmol) at 0° C.; warmed toRT and stirred for 24 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withice-cold water (2 mL) and stirred for 10 min. The pH was adjusted to ˜7with saturated sodium bicarbonate solution. The precipitated solid wasfiltered, washed with water and dried in vacuo to afford 1671 (45 mg,58%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H-NMR(DMSO-d₆, 400 MHz): δ 12.43 (br s, 1H), 11.55 (br s, 1H), 9.48 (br s,1H), 8.77-8.58 (m, 1H), 8.11-7.72 (m, 9H), 4.68-4.63 (m, 2H); LC-MS:96.68%; 494.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.78 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 93.58%; (column; X-select CSH C-18 (150×4.6 mm,3.5 μm); RT 5.70 min. ACN+5% 0.05% TFA: 0.05% TFA+5% ACN; 1.0 mL/min,Diluent: DMSO:ACN:water).

Synthesis of 1878

Synthesis of N-((2-(4-carbamoylphenyl) thiazol-5-yl)methyl)-9-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1878)

To a stirring solution of 1877 (100 mg, 0.19 mmol) in DMSO (2 mL) wereadded potassium carbonate (134 mg, 0.97 mmol) and 30% H₂O₂ (0.22 mL,1.95 mmol) at 0° C.; warmed to RT and stirred for 4 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with water (100 mL), the precipitated solid was filtered anddried in vacuo to afford 1878 (75 mg, 73%) as an off-white solid. TLC:10% MeOH/CH₂Cl₂ (R_(f). 0.3); ¹H-NMR (DMSO-d₆, 400 MHz): δ 10.86 (br s,1H), 9.20 (t, J=5.6 Hz, 1H), 8.07 (br s, 1H), 7.98-7.87 (m, 4H),7.94-7.75 (m, 6H), 7.46 (br s, 1H), 7.34 (d, J=7.9 Hz, 1H), 4.67 (d,J=5.6 Hz, 2H), 2.32 (s, 3H); LC-MS: 98.06%; 533.1 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.87 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.87%;(column; X select CSH C-18 (150×4.6 mm, 3.5 μm); RT 6.99 min. 0.05%TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent: DMSO:ACN:water).

Synthesis of 11106

Synthesis of (3-(4-(5-((5,5-dioxido-11-oxo-10, 11-dihydrodibenzo [b, f][1, 4]thiazepine-8-carboxamido) methyl) thiazol-2-yl)phenoxy)propyl)-L-proline (5) (11106)

To a stirring solution of 11106-A (90 mg, 0.13 mmol) in THF:MeOH:H₂O(2:1:1, 8 mL) was added lithium hydroxide monohydrate (17 mg, 0.40 mmol)at 0° C.; warmed to RT, and stirred for 2 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo and the pH of the residue was acidified with 2 N HCl to pH˜5-6.The obtained solid was filtered, washed with water (20 mL), diethylether (10 mL) and dried in vacuo to obtain 11106 (50 mg, 56%) as anoff-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f). 0.1); ¹H NMR (400 MHz,DMSO-d₆): δ 11.52 (s, 1H), 9.47 (t, J=5.7 Hz, 1H), 8.05 (d, J=8.3 Hz,1H), 8.01-7.95 (m, 2H), 7.93-7.79 (m, 6H), 7.72 (s, 1H), 7.02 (d, J=8.9Hz, 2H), 4.66 (d, J=5.5 Hz, 2H), 4.10 (t, J=6.1 Hz, 2H), 3.52-3.46 (m,2H), 3.18-3.12 (m, 1H), 3.04-2.98 (m, 1H), 2.85-2.78 (m, 1H), 2.20-2.10(m, 1H), 2.06-2.00 (m, 2H), 1.97-1.83 (m, 2H), 1.75-1.65 (m, 1H); LC-MS:95.82%; 647.1 (M+1)⁺; (column; Ascentis Express C-18 (50×3.0 mm, 2.7μm); RT 1.84 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2mL/min); HPLC (purity): 95.18%; (column; X-Select CSH-C-18 (150×4.6 mm,3.5 μm); RT 6.28 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min,Diluent: ACN:H₂O).

Synthesis of 11032-A

Synthesis of tert-butyl (3-((4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenyl) sulfonyl) propyl) carbamate (11032-A)

To a stirring solution of 11007-A (110 mg, 0.16 mmol) in 1, 2 dichloroethane: CH₃CN:H₂O (1:1:2, 4 mL) were added sodium metaperiodate (106 mg,0.49 mmol), ruthenium chloride (1.7 mg, 0.05 mmol) at RT and stirred for16 h. The reaction was monitored by TLC; after completion, the volatileswere removed in vacuo. The residue was diluted with water (50 mL) andextracted with CH₂Cl₂ (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silicagel columnchromatography using 3% MeOH/CH₂Cl₂ to afford 11032-A (15 mg, 13%) aswhite solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400MHz): 11.52 (s, 1H), 9.52 (t, J=5.8 Hz, 1H), 8.15 (d, J=8.4 Hz, 2H),8.01-7.94 (m, 4H), 7.93-7.81 (m, 5H), 7.65 (br s, 1H), 6.90-6.84 (m,1H), 4.73 (d, J=5.6 Hz, 2H), 3.37-3.30 (m, 2H), 2.96 (q, J=5.6 Hz, 2H),1.70-1.59 (m, 2H), 1.33 (s, 9H); LC-MS: 97.78%; 695.1 (M−1)⁺, (column;Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 2.91 min. 2.5 mM Aq. NH₄OOCH+5%ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min). HPLC (purity): 94.67%;(column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 9.28 min. 0.05% TFA(Aq)+5% ACN: ACN+5% 0.5% TFA (Aq); 1.0 mL/min, Diluent: DMSO:ACN:water).

Synthesis of 1583

Synthesis of methyl (5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) glycinate(641)

To a stirring solution of compound 623 (150 mg, 0.49 mmol) in DMF (10mL) under inert atmosphere were added EDCI.HCl (179 mg, 0.99 mmol), HOBt(133 mg, 0.99 mmol) and diisopropylethylamine (0.45 mL, 5.00 mmol) andmethyl (5-(aminomethyl) thiazol-2-yl) glycinate hydrochloride 92 (109mg, 0.55 mmol) at 0° C.; warmed to RT and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with water (50 mL) and extracted with EtOAc (2×100mL). The combined organic extracts were washed with water (50 mL), brine(50 mL), dried over sodium sulfate, filtered and concentrated in vacuoto obtain the crude. The crude was triturated with diethyl ether: CH₃CN(4:1, 10 mL) and the obtained solid was dried in vacuo to afford 641 (85mg, 35%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4);¹H-NMR (DMSO-d₆ 400 MHz): δ 11.50 (s, 1H), 9.23 (t, J=5.7 Hz, 1H), 8.03(d, J=8.3 Hz, 1H), 7.98 (dd, J=9.3, 1.8 Hz, 2H), 7.93-7.81 (m, 4H), 7.77(dd, J=8.3, 1.5 Hz, 1H), 6.88 (s, 1H), 4.40 (d, J=5.6 Hz, 2H), 3.99 (d,J=6.2 Hz, 2H), 3.61 (s, 3H).

Synthesis of (5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b, f] [1,4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) glycine (1583)

To a stirring solution of compound 641 (70 mg, 0.14 mmol) in THF:H₂O(3:1, 8 mL) was added lithium hydroxide monohydrate (13.8 mg, 0.28 mmol)at RT and stirred for 6 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(50 mL) and washed with EtOAc (2×50 mL). The pH of the aqueous layer wasacidified with 4 N HCl to ˜2. The precipitated solid was filtered anddried in vacuo to afford 1583 (37 mg, 54%) as an off-white solid. TLC:10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ 12.50 (br s,1H), 11.49 (s, 1H), 9.23 (t, J=5.4 Hz, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.98(td, J=7.4, 0.9 Hz, 2H), 7.90 (td, J=7.5, 1.3 Hz, 1H), 7.87-7.81 (m,2H), 7.77 (dd, J=8.2, 1.2 Hz, 1H), 7.73 (t, J=5.7 Hz, 1H), 6.88 (s, 1H),4.40 (d, J=5.5 Hz, 2H), 3.88 (d, J=6.0 Hz, 2H); LC-MS: 95.64%; 472.9(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.75 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC(purity): 97.00%; (column; Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT 4.87min. ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0 mL/min).

Synthesis of 1580

Synthesis of 2-((5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b, f][1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) oxy) acetic acid(1580)

To a stirring suspension of added sodium hydride (60%, 27.7 mg, 1.15mmol) in THF (15 mL) under argon atmosphere was added ethyl2-hydroxyacetate 642 (48 mg, 0.46 mmol) at 0° C. and stirred for 1 h. Tothis was added compound 535 (100 mg, 0.23 mmol) at 0° C.; heated to 60°C. and stirred for 16 h. The reaction was monitored by TLC and LC-MS;after completion of the reaction, the reaction mixture was diluted withwater (20 mL) and the extracted with EtOAc (2×10 mL). The pH of theaqueous layer was adjusted to ˜4 using 2 N HCl and extracted with 5%MeOH/CH₂Cl₂ (3×50 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude compound was purified by preparative HPLC purification toafford 1580 (10 mg, 9%) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂+0.1mL CH₃COOH (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 9.32 (br s, 1H),8.03 (d, J=8.3 Hz, 1H), 7.98 (td, J=7.4, 1.1 Hz, 2H), 7.93-7.82 (m, 4H),7.78 (dd, J=8.3, 1.6 Hz, 1H), 7.00 (s, 1H), 4.49 (br s, 2H), 4.45 (d,J=4.7 Hz, 2H); LC-MS: 95.67%; 473.8 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 1.96 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 94.09%; (column; X-selectCSH C-18 (150×4.6 mm, 3.5 μm); RT 7.17 min. ACN: 0.05% TFA (Aq); 1.0mL/min).

Synthesis of 1586

Synthesis of N-((2-(2-(dimethylamino) ethoxy) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1586)

To a stirring solution of 2-(dimethylamino) ethan-1-ol 643 (62 mg, 0.69mmol) in dry THF (10 mL) was added sodium hydride (60%, 25 mg, 0.69mmol) under argon atmosphere was added at 0° C. and stirred for 10 min.To this was added N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide535 (150 mg, 0.34 mmol) at 0° C.; heated to 60° C. and stirred for 24 h.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with ice-cold water (20 mL) and theextracted with EtOAc (2×10 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel column chromatographyusing 10% MeOH/CH₂Cl₂ to afford compound to afford 1586 (40 mg, 24%) asan off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆,400 MHz): δ 11.51 (br s, 1H), 9.36 (t, J=5.6 Hz, 1H), 8.05 (d, J=8.4 Hz,1H), 8.01-7.95 (m, 2H), 7.93-7.83 (m, 3H), 7.78 (dd, J=8.2, 1.3 Hz, 1H),7.08 (s, 1H), 4.47 (d, J=5.8 Hz, 2H), 4.43 (t, J=5.5 Hz, 2H), 2.81-2.73(m, 2H), 2.28 (s, 6H); LC-MS: 95.67%; 487.0 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.58 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.75%; (column;Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT 5.23 min. ACN: 0.05% TFA (Aq);1.0 mL/min).

Synthesis of 1680

Synthesis of N-((2-(3-(dimethylamino) propoxy) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1680)

To a stirring suspension of 3-(dimethylamino) propan-1-ol 644 (57 mg,0.55 mmol) in THF (20 mL) under argon atmosphere was added sodiumhydride (60%, 55 mg, 1.38 mmol) at 0° C. and stirred for 20 min. To thiswas added N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo[b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide 535 (200 mg, 0.46mmol) at 0° C.; heated to 50-60° C. and stirred for 12 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was quenched with saturated citric acid solution (10 mL) andextracted with 10% n-butanol/EtOAc (2×40 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through basic aluminaflash column chromatography using 5% MeOH/CH2Cl2, triturated with 20%CH2Cl2/n-pentane (10 mL) and dried in vacuo to afford 1680 (80 mg, 35%)as white solid. TLC: 10% MeOH/CH2Cl2 (R_(f): 0.2); 1H-NMR (DMSO-d6, 400MHz): δ 11.50 (br s, 1H), 9.33 (t, J=5.7 Hz, 1H), 8.04 (d, J=8.3 Hz,1H), 8.01-7.95 (m, 2H), 7.90 (td, J=7.5, 1.5 Hz, 1H), 7.86 (dd, J=7.5,1.6 Hz, 1H), 7.83 (s, 1H), 7.78 (dd, J=8.3, 1.5 Hz, 1H), 7.07 (s, 1H),4.46 (d, J=5.5 Hz, 2H), 4.32 (t, J=6.5 Hz, 2H), 2.28 (t, J=7.0 Hz, 2H),2.10 (s, 6H), 1.87-1.79 (m, 2H); LC-MS: 95.84%; 501.0 (M++1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.70 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 94.58%;(column; Zorbax SBC C-18 (150×4.6 mm, 3.5 μm); RT 5.73 min. ACN: 0.05%TFA (Aq); 1.0 mL/min, Diluent: ACN:water).

Synthesis of 1660

Synthesis of N-((2-chlorothiazol-5-yl) methyl)-N-methyl-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(645)

To a stirring solution of 92 (200 mg, 0.66 mmol) in DMF (10 mL) underinert atmosphere were added EDCI.HCl (190 mg, 0.99 mmol), HOBt (133 mg,0.99 mmol), compound 368 (117 mg, 0.72 mmol) and diisopropylethylamine(0.36 mL, 1.98 mmol) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (70 mL) and extracted with EtOAc(2×50 mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silicagel column chromatography using 5% MeOH/CH₂Cl₂ toafford compound 645 (100 mg, 33%) as an off-white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.6); ¹H NMR (DMSO-d₆, 400 MHz): δ 11.44 (br s, 1H),8.03-7.96 (m, 3H), 7.93-7.83 (m, 2H), 7.72 (s, 1H), 7.46-7.39 (m, 2H),4.75 (s, 2H), 2.85 (s, 3H); LC-MS: 96.84%; 448.0 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.19 min. 0.025% Aq.TFA+5%ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-((2-(2-(dimethylamino) ethoxy) thiazol-5-yl)methyl)-N-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1660)

To a stirring solution of 2-(dimethylamino) ethan-1-ol 643 (176 mg, 0.98mmol) in THF (20 mL) under argon atmosphere was added sodium hydride(60%, 47 mg, 1.98 mmol) at 0° C. and stirred for 20 min. To this wasadded compound 645 (300 mg, 0.99 mmol) at 0° C.; heated to 60° C. andstirred for 6 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was quenched with ice-cold water (1mL). The volatiles were removed in vacuo to obtain the crude. The crudecompound was purified through basis alumina column chromatography using3% MeOH/CH₂Cl₂ to afford 1660 (20 mg, 4%) as an off-white solid. TLC:10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz) (rotamers): δ11.43 (br s, 1H), 8.04-7.96 (m, 3H), 7.94-7.83 (m, 2H), 7.44-7.37 (m,2H), 7.19, 7.01 (s, 1H), 4.63 (s, 1.5H), 4.41 (t, J=5.4 Hz, 2.5H), 2.91,2.81 (s, 3H), 2.65-2.60 (m, 2H), 2.19 (s, 6H); LC-MS: 95.12%; 501.0(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.71 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC(purity): 97.19%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT5.09 min. ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0 mL/min,Diluent: ACN:water).

Synthesis of 1589

Synthesis of methyl 2-((5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo[b, f] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) thio)acetate (647)

To a stirring solution of compound 92 (200 mg, 0.66 mmol) in DMF (5 mL)under inert atmosphere were added EDCI.HCl (179 mg, 0.99 mmol), HOBt(133 mg, 0.99 mmol) and diisopropylethylamine (0.4 mL, 1.76 mmol) andmethyl 2-((5-(aminomethyl) thiazol-2-yl) thio) acetate hydrochloride 646(183 mg, 0.73 mmol) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (50 mL), the precipitated solidwas filtered and dried in vacuo to afford compound 647 (160 mg, 48%) aspale brown solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆ 500MHz): δ 11.50 (s, 1H), 9.41 (t, J=5.6 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H),7.98 (t, J=8.4 Hz, 2H), 7.90 (t, J=7.1 Hz, 1H), 7.88-7.82 (m, 2H), 7.78(d, J=8.1 Hz, 1H), 7.59 (s, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.12 (s, 2H),3.64 (s, 3H).

Synthesis of 2-((5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b, f][1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) thio) acetic acid(1589)

To a stirring solution of compound 647 (100 mg, 0.19 mmol) in THF:H₂O(1:1, 10 mL) was added lithium hydroxide monohydrate (10 mg, 0.28 mmol)at RT and stirred for 6 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. The pHof the residue was acidified with 4 N HCl to ˜4. The precipitated solidwas filtered and dried in vacuo to afford 1589 (60 mg, 51%) as anoff-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500MHz): δ 12.89 (br s, 1H), 11.50 (s, 1H), 9.41 (t, J=5.4 Hz, 1H), 8.04(d, J=8.4 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.81 (m, 3H), 7.78 (d, J=8.4Hz, 1H), 7.58 (s, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.02 (s, 2H); LC-MS:98.73%; 490.0 (M⁺+1); (column; X-select CSH C18, (50×3.0 mm, 2.5 μm); RT2.10 min. 2.5 mM Aq.NH₄OOCH+5% ACN+5% 2.5 mM Aq.NH₄OOCH; 0.0.8 mL/min);HPLC (purity): 99.17%; (column; Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT6.59 min. ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0 mL/min).

Synthesis of 1585

Synthesis of methyl 4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) benzoate (648)

To a stirring solution of compound 92 (200 mg, 0.66 mmol) in DMF (10 mL)under inert atmosphere were added EDCI.HCl (189.1 mg, 0.99 mmol), HOBt(133.6 mg, 0.99 mmol) at RT and stirred for 5 min. To this was addedmethyl 4-(5-(aminomethyl) thiazol-2-yl) benzoate hydrochloride 636(196.4 mg, 0.79 mmol) and diisopropylethylamine (0.59 mL, 3.29 mmol) atRT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted withice-cold water (100 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel flash column chromatography using 2% MeOH/CH₂Cl₂ toafford compound 648 (130 mg, 37%) as an off-white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H-NMR (DMSO-d₆, 500 MHz): δ 11.52 (br s, 1H),9.51 (t, J=5.6 Hz, 1H), 8.08-8.01 (m, 5H), 7.98 (t, J=8.5 Hz, 2H),7.92-7.80 (m, 5H), 4.71 (d, J=5.8 Hz, 2H), 3.87 (s, 3H).

Synthesis of 4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b, f] [1,4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) benzoic acid (1585)

To a stirring solution of compound 648 (80 mg, 0.15 mmol) in THF:H₂O(5:1, 6 mL) was added lithium hydroxide monohydrate (19 mg, 0.45 mmol)at 0° C.; warmed to RT and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, volatiles were removed invacuo. The crude was washed with EtOAc (2×10 mL). The obtained solid wasdissolved in water (20 mL) and pH was adjusted to ˜2 using 2 N HCl. Theprecipitated solid was filtered, washed with water (20 mL), n-pentane(50 mL) and dried in vacuo to afford 1585 (60 mg, 77%) as an off-whitesolid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ13.18 (br s, 1H), 11.52 (s, 1H), 9.51 (t, J=5.6 Hz, 1H), 8.09-7.95 (m,7H), 7.93-7.80 (m, 5H), 4.71 (d, J=5.8 Hz, 2H); LC-MS: 92.54%; 519.9(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.22 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC(purity): 93.48%; (column; Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT 7.41min. ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0 mL/min).

Synthesis of 1645-B

Synthesis of (2-(4-nitrophenyl) thiazol-5-yl) methanamine hydrochloride(649)

To a stirring solution of tert-butyl ((2-(4-nitrophenyl) thiazol-5-yl)methyl) carbamate 309 (150 mg, 0.44 mmol) in CH₂Cl₂ (5 mL) under inertatmosphere was added 4 N HCl in 1, 4-dioxane (1.5 mL) at 0° C.; warmedto RT and stirred for 2 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo toobtain the crude. The crude was washed with diethylether (2×5 mL) anddried in vacuo to afford compound 649 (110 mg, 91%) as yellow solid.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ 8.52 (brs, 3H), 8.36 (d, J=9.0 Hz, 2H), 8.21 (d, J=9.0 Hz, 2H), 8.12 (s, 1H),4.41 (br s, 2H).

Synthesis of N-((2-(4-nitrophenyl) thiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(650)

To a stirring solution of 92 (100 mg, 0.33 mmol) in DMF (5 mL) underinert atmosphere were added EDCI.HCl (95 mg, 0.49 mmol), HOBt (67 mg,0.49 mmol), compound 649 (108 mg, 0.39 mmol) and diisopropylethylamine(0.18 mL, 0.99 mmol) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (50 mL) and extracted with EtOAc(2×100 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silicagel column chromatography using 3%MeOH/CH₂Cl₂ to afford compound 650 (80 mg, 47%) as an off-white solid.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H NMR (DMSO-d₆, 500 MHz): δ11.52 (brs, 1H), 9.53 (t, J=5.5 Hz, 1H), 8.31 (d, J=8.7 Hz, 2H), 8.15 (d, J=8.7Hz, 2H), 8.06 (d, J=8.4 Hz, 1H), 8.01-7.95 (m, 3H), 7.92-7.79 (m, 4H),4.73 (d, J=5.5 Hz, 2H); LC-MS: 93.76%; 520.9 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.46 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-((2-(4-aminophenyl) thiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(1645-B)

To a stirring solution of compound 650 (75 mg, 0.14 mmol) in MeOH (10mL) under inert atmosphere was added 10% Pd/C (30 mg) at RT and stirredunder hydrogen atmosphere (balloon pressure) at RT for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite and washed with MeOH (100mL). The filtrate was concentrated in vacuo to obtain the crude, whichwas titurated with diethyl ether:n-pentane (1:1, 20 mL) and followed bysilicagel column chromatography using 2-3% MeOH/CH₂Cl₂ to afford 1645-B(22 mg, 32%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2);41 NMR (DMSO-d₆, 400 MHz): δ 11.48 (br s, 1H), 9.40 (t, J=5.5 Hz, 1H),8.05 (d, J=8.3 Hz, 1H), 7.98 (td, J=7.5, 0.9 Hz, 2H), 7.94-7.78 (m, 4H),7.59 (s, 1H), 7.53 (d, J=8.5 Hz, 2H), 6.57 (d, J=8.6 Hz, 2H), 5.62 (s,2H), 4.62 (d, J=5.5 Hz, 2H); LC-MS: 97.21%; 491.0 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.97 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.45%;(column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 9.06 min. ACN+5 mMNH₄OAc: ACN; 1.0 mL/min, Diluent: ACN:water).

Synthesis of 1764

Synthesis of N-((2-(4-cyanophenyl) thiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(651)

To a stirring solution of 92 (300 mg, 0.99 mmol) in DMF (15 mL) underinert atmosphere were added EDCI.HCl (283 mg, 1.48 mmol), HOBt (200 mg,1.48 mmol), compound 227 (274 mg, 1.08 mmol) and diisopropylethylamine(0.55 mL, 2.95 mmol) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with ice-cold water (100 mL) and extractedwith EtOAc (2×150 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silicagel column chromatography using 3%MeOH/CH₂Cl₂ to afford compound 651 (250 mg, 50%) as white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.6); ¹H NMR (DMSO-d₆, 400 MHz): δ 11.52 (s, 1H),9.52 (t, J=5.7 Hz, 1H), 8.08-7.79 (m, 11H), 4.72 (d, J=5.6 Hz, 2H);LC-MS: 99.46%; 501.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 2.30 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of N-((2-(4-carbamoylphenyl) thiazol-5-yl) methyl)-11-oxo-10,11 dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(1764)

To a stirring solution of compound 651 (100 mg, 0.20 mmol) in EtOH (5mL) were added 30% H₂O₂ (5 mL) and 30% aqueous ammonia (5 mL) at 0° C.warmed to RT and stirred for 2 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (100 mL) and extracted with CH₂Cl₂ (2×50 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was washed with EtOAc (2×10 mL) anddried in vacuo to afford 1764 (55 mg, 53%) as white solid. TLC: 7%MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.48 (br s, 1H),9.50 (t, J=5.8 Hz, 1H), 8.08-8.04 (m, 2H), 8.00-7.94 (m, 6H), 7.90 (td,J=7.5, 1.4 Hz, 1H), 7.87-7.80 (m, 4H), 7.44 (br s, 1H), 4.71 (d, J=5.6Hz, 2H); LC-MS: 98.11%; 519.0 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 1.98 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min); HPLC (purity): 98.61%; (column; X select CSH C-18(150×4.6 mm, 3.5 μm); RT 6.87 min. ACN+5% 0.05% TFA (Aq): 0.05% TFA(Aq)+5% ACN; 1.0 mL/min, Diluent: ACN:water).

Synthesis of 1666 and 1669

Synthesis of N-((2-(6-methoxypyridin-3-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1666)

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide535 (300 mg, 0.69 mmol) in 1, 2 dimethoxy ethane:H₂O (4:1, 10 mL) wereadded (6-methoxypyridin-3-yl) boronic acid 582 (127 mg, 0.84 mmol),sodium carbonate (220 mg, 2.07 mmol) in a sealed tube and purged underargon atmosphere for 15 min. To this was added Pd(PPh₃)₄ (80 mg, 0.069mmol) at RT; heated to 110° C. and stirred for 16 h. The reaction wasmonitored by TLC; after completion the reaction mixture was diluted withwater (50 mL) and extracted with 5% MeOH/CH₂Cl₂ (100 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 2-8% MeOH/CH₂Cl₂ toafford compound 1666 (140 mg, 27%) as an off-white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 500 MHz): δ 11.52 (s, 1H),9.47 (t, J=6.1 Hz, 1H), 8.68 (d, J=2.3 Hz, 1H), 8.16 (dd, J=8.7, 2.3 Hz,1H), 8.06 (d, J=8.1 Hz, 1H), 7.98 (t, J=8.2 Hz, 2H), 7.93-7.78 (m, 5H),6.92 (d, J=8.7 Hz, 1H), 4.68 (d, J=5.5 Hz, 2H), 3.90 (s, 3H); LC-MS:96.23%; 507.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 2.23 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min) HPLC (purity): 94.46%; (column; X-select CSH C-18 (150×4.6 mm,3.5 μm); RT 8.40 min. ACN+5% 0.5% TFA (Aq): 0.5% TFA (Aq)+5% ACN; 1.0mL/min, Diluent: ACN:water).

Synthesis of N-((2-(6-hydroxypyridin-3-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1669)

To a stirring solution of 1666 (100 mg, 0.19 mmol) in DMF (5 mL) underinert atmosphere were added lithium chloride (43 mg, 0.99 mmol),p-toluene sulfonic acid (4 mg, 0.019 mmol) at RT in a sealed tube;heated to 110° C. and stirred for 16 h. The reaction was monitored byTLC and LC-MS; after completion the reaction mixture was diluted withwater (50 mL) and the precipitated was filtered, washed with CH₂Cl₂ (5mL) and dried in vacuo to afford 1669 (60 mg, 62%) as an off-whitesolid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 500 MHz): δ11.96 (br s, 1H), 11.52 (br s, 1H), 9.45 (t, J=5.2 Hz, 1H), 8.05 (d,J=8.1 Hz, 1H), 7.98 (t, J=8.1 Hz, 2H), 7.94-7.83 (m, 5H), 7.80 (d, J=8.1Hz, 1H), 7.68 (s, 1H), 6.43 (d, J=9.5 Hz, 1H), 4.64 (d, J=5.5 Hz, 2H);LC-MS: 97.01%; 492.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 1.83 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 93.66%; (column; Zorbax SBC C-18 (150×4.6 mm,3.5 μm); RT 5.81 min. ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0mL/min, Diluent: DMSO:ACN:water).

Synthesis of 1880 & 1880-A

Synthesis of 4-methoxy-2-(tributylstannyl) pyridine (653)

To a stirring solution of 2-bromo-4-methoxypyridine 652 (1 g, 5.39 mmol)in dry Toluene (40 mL) under inert atmosphere was added n-butyl lithium(3.98 mL, 6.38 mmol, 1.6 M solution in hexane) at −78° C. and stirredfor 1 h. To this was added tributyltin chloride (7.85 mL, 28.98 mmol) at−78° C.; warmed to RT and stirred for 30 min. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasquenched with ice-cold water (50 mL) and extracted with EtOAc (2×100mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to afford compound 653 (1.5 g, 71%)as yellow liquid which was taken for next step without furtherpurification. TLC: 20% EtOAc/hexanes (R_(f): 0.8);

Synthesis of N-((2-(4-methoxypyridin-2-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1880-A)

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, 1] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide535 (500 mg, 1.15 mmol) in 1, 4-dioxane (30 mL) under argon atmospherewere added compound 653 (1.37 g, 3.46 mmol) and purged under argonatmosphere for 30 min, added Pd(dppf)Cl₂ (84 mg, 0.11 mmol) and heatedto 110° C. and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 3% MeOH/CH₂Cl₂ to afford 1880-A (125 mg, 21%) as anoff-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H-NMR (DMSO-d₆, 400MHz): δ 11.51 (s, 1H), 9.47 (t, J=5.8 Hz, 1H), 8.40 (d, J=5.6 Hz, 1H),8.06 (d, J=8.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.90 (td, J=7.5, 1.4 Hz, 1H),7.87-7.83 (m, 3H), 7.81 (dd, J=8.3, 1.5 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H),7.04 (dd, J=5.7, 2.6 Hz, 1H), 4.69 (d, J=5.6 Hz, 2H), 3.90 (s, 3H);LC-MS: 97.10%; 507.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 2.05 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 96.24%; (column; X-select CSH C-18 (150×4.6 mm,3.5 μm); RT 7.21 min. 0.05% TFA (Aq)+5% ACN: ACN+5% 0.05% ACN; 1.0mL/min, Diluent: DMSO:ACN:water).

Synthesis of N-((2-(4-hydroxypyridin-2-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1880)

To a stirring solution of 1880-A (120 mg, 0.23 mmol) in DMF (10 mL)under inert atmosphere were added lithium chloride (206 mg, 4.74 mmol),p-toluenesulfonic acid (20 mg, 0.11 mmol) at RT; heated to 120-130° C.and stirred for 24 h. The reaction was monitored by TLC and LC-MS; aftercompletion the reaction mixture was poured into ice-cold water (50 mL)and extracted with EtOAc (2×150 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography twice using 3% MeOH/CH₂Cl₂ to afford 1880 (15 mg, 13%) asan off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆,400 MHz): δ 11.51 (br s, 1H), 10.96 (br s, 1H), 9.48-9.43 (m, 1H), 8.26(br d, J=3.5 Hz, 1H), 8.06 (br d, J=8.2 Hz, 1H), 7.98 (br t, J=7.3 Hz,2H), 7.93-7.78 (m, 5H), 7.46 (br s, 1H), 6.81 (s, 1H), 4.68 (br d, J=4.1Hz, 2H); LC-MS: 99.60%; 492.9 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 1.76 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min); HPLC (purity): 99.70%; (column; X-select CSH C-18(150×4.6 mm, 3.5 μm); RT 5.94 min. 0.05% TFA (Aq)+5% ACN: ACN+5% 0.05%ACN; 1.0 mL/min, Diluent: DMSO:ACN:water).

Synthesis of 1889

Synthesis of 2-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1,4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) pyridin-4-yltrifluoromethanesulfonate (654)

To a stirring solution of 1880 (200 mg, 0.40 mmol) in CH₂Cl₂ (10 mL)under inert atmosphere were added triethyl amine (1.67 mL, 1.21 mmol),triflic anhydride (0.1 mL, 0.60 mmol) at 0° C.; and stirred for 30 min.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with ice-cold water (30 mL) and extractedwith CH₂Cl₂ (2×40 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to afford compound654 (210 mg crude) as an off white solid. The crude was taken forwardnext reaction without further purification. TLC: 5% MeOH/CH₂Cl₂ (R_(f).0.7); LC-MS: 41%; 624.9 (M⁺+1); (column; Ascentis Express C-18, (50×3.0mm, 2.7 μm); RT 2.56 min, 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min);

Synthesis of N-((2-(4-(dimethylamino) pyridin-2-yl) thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5,5-dioxide (1889)

To a stirring solution of compound 654 (210 mg crude, 0.33 mmol) in THF(5 mL) in a sealed tube was added 2 M dimethylamine in THF (0.36 mL,0.67 mmol) at RT and stirred for 16 h. The reaction was monitored byTLC; after completion the volatiles were removed in vacuo to obtain thecrude. The crude was purified through silica gel column chromatographyusing 3-4% MeOH/CH₂Cl₂ and further purified by preparative HPLCpurification to afford 1889 (10 mg, 6%) as an off-white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.54 (s, 1H),9.56 (br s, 1H), 8.10 (dd, J=16.7, 7.6 Hz, 2H), 7.98 (td, J=7.4, 1.1 Hz,3H), 7.93-7.81 (m, 4H), 7.30 (d, J=2.6 Hz, 1H), 6.88 (br s, 1H), 4.74(br d, J=5.5 Hz, 2H), 3.17 (br s, 6H); LC-MS: 95.94%; 520.0 (M⁺+1);(column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 2.47 min. 2.5 mM Aq.NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq. NH₄OOCH, 0.8 mL/min). HPLC (purity):99.48%; (column; X select CSH C-18 (150×4.6 mm, 3.5 μm); RT 5.73 min.0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent:DMSO:ACN:water).

Synthesis of 1886

Synthesis of tert-butyl (6-bromopyridin-3-yl) carbamate (656)

To a stirring solution of 6-bromopyridin-3-amine 655 (5 g, 28.90 mmol)in CH₂Cl₂ (50 mL) under argon atmosphere were added Boc-anhydride (7.6g, 34.86 mmol) and triethylamine (6.17 mL, 43.35 mmol) at 0 to 10° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (100 mL), filtered through celite and eluted with CH₂Cl₂ (3×80mL). The filtrate was dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel flash column chromatography using 5-7% EtOAc/hexanesto afford compound 656 (5 g, 64%) as white solid. TLC: 20% EtOAc/hexanes(R_(f): 0.8); ¹H-NMR (DMSO-d₆, 500 MHz): δ 9.72 (br s, 1H), 8.45 (s,1H), 7.82 (dd, J=8.4, 2.0 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 1.48 (s, 9H);LC-MS: 91.60%; 272.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 2.48 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of tert-butyl (6-(tributylstannyl) pyridin-3-yl) carbamate(657)

To a stirring solution of compound 656 (5 g, 18.31 mmol) in THF (50 mL)under argon atmosphere was added n-butyl lithium (23 mL, 36.63 mmol, 1.6M solution in hexane) dropwise for 40 min at −78° C. and warmed to −10°C. and stirred for 40 min. To this was added tributylchlorostannane(8.92 g, 27.47 mmol) in THF (10 mL) at −78° C. and stirred for 1 h atthe same temperature. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withsaturated ammonium chloride solution (50 mL) and extracted with EtOAc(2×200 mL). The combined organic extracts were washed with saturatedpotassium fluoride solution (100 mL), dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silicagel flash column chromatography using 5-7%EtOAc/hexanes to afford compound 657 (3 g, 34%) as yellow solid. TLC:20% EtOAc/hexanes (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 9.42 (s,1H), 8.70 (s, 1H), 7.73 (dd, J=8.0, 2.3 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H),1.64-1.54 (m, 6H), 1.47 (s, 9H), 1.38-1.22 (m, 6H), 1.14-1.08 (m, 6H),0.87 (t, J=7.3 Hz, 9H); The aliphatic region shows tin reagent asimpurity; LC-MS: 68.59%; 485.2 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 2.78 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl (6-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) pyridin-3-yl) carbamate (658)

To a stirring solution of compound 535 (200 mg, 0.46 mmol) in 1,4-dioxane (10 mL) under inert atmosphere were added compound 657 (670mg, 1.38 mmol) and purged under argon atmosphere for 15 min, addedPd(dppf)Cl₂ (34 mg, 0.046 mmol) and heated to 100° C. and stirred for 16h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was filtered through celite washed with EtOAc (2×50mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel flash column chromatography using 2-5%MeOH/CH₂Cl₂. The obtained compound was precipitated using 20%EtOAc/hexanes to afford compound 658 (50 mg, 18%) as an off-white solid.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.50 (s,1H), 9.81 (s, 1H), 9.44 (t, J=5.5 Hz, 1H), 8.59 (s, 1H), 8.07-7.76 (m,10H), 4.66 (d, J=5.3 Hz, 2H), 1.48 (s, 9H); LC-MS: 96.84%; 592.1 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.43 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-((2-(5-aminopyridin-2-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1886)

To a stirring solution of compound 658 (50 mg, 0.08 mmol) in CH₂Cl₂ (5mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under argon atmosphere at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The compound was dissolved in CH₂Cl₂ (1 mL)and precipitated using n-hexane (10 mL) to afford 35 mg of semi-purifiedmaterial. This was further purified by precipitation in N-methylpyrrolidinone: H₂O (1:20, 21 mL) and stirred for 16 h. The solidobtained was filtered and dried in vacuo to afford 1886 (25 mg, 61%) asan off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H-NMR (DMSO-d₆,400 MHz): δ 11.52 (s, 1H), 9.43 (t, J=5.6 Hz, 1H), 8.05 (d, J=8.3 Hz,1H), 7.98 (td, J=7.6, 1.1 Hz, 2H), 7.93-7.79 (m, 5H), 7.77 (d, J=8.5 Hz,1H), 7.68 (s, 1H), 7.02 (dd, J=8.5, 2.6 Hz, 1H), 4.63 (d, J=5.6 Hz, 2H);LC-MS: 94.26%; 492.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 2.26 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min). HPLC (purity): 93.39%; (column; X-select CSH-C18 (150×4.6 mm,3.5 μm); RT 8.69 min. 5 mM NH4OAc: ACN; 1.0 mL/min, Diluent:DMSO:ACN:water).

Synthesis of 1888

Synthesis of tert-butyl (2-bromopyridin-4-yl) carbamate (660)

To a stirring solution of 2-bromopyridin-4-amine 659 (5 g, 28.90 mmol)in 1, 2-dichloro ethane (80 mL) under inert atmosphere were addedtriethylamine (9.53 mL, 86.70 mmol) Boc-anhydride (7.56 g, 34.67 mmol)at 0° C.; heated to 70° C. and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction thevolatiles were concentrated in vacuo. The residue was diluted CH₂Cl₂ (20mL), washed with water (100 mL). The organic extract was dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel flash column chromatographyusing 5-20% EtOAc/hexanes to afford compound 660 (3.5 g, 44%) as an offwhite solid. TLC: 40% EtOAc/hexanes (R_(f): 0.7); LC-MS: 99.62%; 274.8(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.40 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl (2-(triisopropoxy-14-boranyl) pyridin-4-yl)carbamate, lithium salt (661)

To a stirring solution of tert-butyl (2-bromopyridin-4-yl) carbamate 660(5 g, 18.31 mmol) and triisopropyl borate (1.52 mL, 6.55 mmol) in drytoluene: THF (4:1; 100 mL) under inert atmosphere was added n-butyllithium (2.5 M solution in hexane, 24.92 mL, 5.46 mmol) drop wise for1.5 h at −78° C. and stirred for 30 min. To this was added triisopropylborate (4.13 g, 21.97 mmol) and warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo to afford compound 661 (7.2 g crudesalt) as yellow solid. The crude was carried forward for next reactionwithout purification. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.1);

Synthesis of tert-butyl (2-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) pyridin-4-yl) carbamate (662)

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, 1] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide535 (2 g, 4.61 mmol) in 1, 2 dimethoxy ethane: H₂O (4:1, 80 mL) wereadded sodium carbonate (1.46 g, 13.85 mmol), compound 661 (7.37 g crude)and purged under argon atmosphere for 20 min. To this was addedPd(dppf)Cl₂ (337 mg, 0.46 mmol) at RT; heated to 100° C. and stirred for16 h. The reaction was monitored by TLC; after completion of thereaction; the reaction mixture was filtered through celite and washedwith 10% MeOH/CH₂Cl₂ (2×100 mL). The filtrate was concentrated in vacuoto obtain the crude. The crude was purified through silica gel flashcolumn chromatography using 3% MeOH/CH₂Cl₂ to afford compound 662 (380mg) as brown solid. LC-MS: 67.12%; 542 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 2.20 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min);

Synthesis of N-((2-(4-aminopyridin-2-yl) thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5,5-dioxide, TFA Salt (1888)

To a stirring solution of compound 662 (380 mg crude) in CH₂Cl₂ (15 mL)under inert atmosphere was added 4 N HCl in 1, 4-dioxane (4 mL) at 0°C.; warmed to RT and stirred for 3 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The crude was triturated with diethyl ether (5 mL), n-pentane (10 mL)and further purified by preparative HPLC purification to afford 1888 (45mg, 14%) as an off-white solid. ¹H-NMR (DMSO-d₆, 400 MHz): δ 13.68 (brs, 1H), 11.55 (s, 1H), 9.65-9.56 (m, 1H), 8.10-8.02 (m, 3H), 7.98 (br t,J=7.3 Hz, 2H), 7.91 (td, J=7.0, 1.1 Hz, 1H), 7.88-7.80 (m, 3H), 7.29 (d,J=2.1 Hz, 1H), 6.78 (br d, J=5.3 Hz, 1H), 4.75 (br d, J=5.6 Hz, 2H);LC-MS: 99.93%; 492.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 1.62 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 99.71%; (column; X select CSH C-18 (150×4.6 mm,3.5 μm); RT 5.27 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min,Diluent: DMSO:ACN:water).

Synthesis of 11019 & 11019-A

Synthesis of tert-butyl 4-(5-bromopyridin-2-yl) piperazine-1-carboxylate(665)

To a stirring solution 2, 5-dibromopyridine 663 (500 mg, 2.11 mmol) inN-methyl pyrrolidinone (2 mL) under inert atmosphere was addedtert-butyl piperazine-1-carboxylate 664 (786 mg, 4.2 mmol) in a sealedtube and heated to 140° C. and stirred for 16 h. The reaction wasmonitored by TLC and LC-MS; after completion the reaction mixture wasdiluted with EtOAc (100 mL) and washed with water (50 mL). The organicextract was dried over sodium sulphate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 30% EtOAc/hexanes to afford compound 665(400 mg, 56%) as an off-white solid. TLC: 30% EtOAc/hexanes (R_(f):0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.18 (d, J=2.3 Hz, 1H), 7.70 (dd,J=9.3, 2.6 Hz, 1H), 6.83 (d, J=9.0 Hz, 1H), 3.49-3.44 (m, 4H), 3.42-3.37(m, 4H), 1.42 (s, 9H); LC-MS: 99.81%; 341.9 (M⁺+1); (column; Kinetex EVOC-18 (50×3.0 mm, 2.6 um); RT 3.62 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5%2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of tert-butyl 4-(5-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) pyridin-2-yl) piperazine-1-carboxylate (666)

To a stirring solution of compound 665 (400 mg, 1.16 mmol) in 1,4-dioxane (25 mL) under inert atmosphere were added bispinacolatodiboron (594 mg, 2.33 mmol), potassium acetate 343 mg, 3.50 mmol) at RTand purged under argon atmosphere for 15 min; to this was addedPd(dppf)Cl₂ (85 mg, 0.11 mmol) and purged under argon atmosphere for 5min, heated to reflux and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles wereconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 10-50% EtOAc/hexanes toafford compound 666 (420 mg, 43%) as an off-white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.4); LC-MS: 98.83%; 307.9 (M⁺+1) (Boronic acid);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.60 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl 4-(5-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) pyridin-2-yl) piperazine-1-carboxylate (11019-A)

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide535 (300 mg, 0.73 mmol) in 1, 4-dioxane: H₂O (4:1, 12 mL) under inertatmosphere were added compound 666 (410 mg, 1.46 mmol), cesium carbonate(714 mg, 2.19 mmol) in a sealed tube at RT and purged under argonatmosphere for 15 min, added Pd(dppf)Cl₂ (54 mg, 0.073 mmol) and heatedto 110° C. and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the reaction was monitored by TLC;after completion of the reaction, the volatiles were concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 10-50% EtOAc/hexanes, triturated usingCH₂Cl₂: hexanes (10 mL) and dried in vacuo to afford 11019-A (150 mg,33%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.44 (t, J=5.8 Hz, 1H), 8.61 (d,J=2.1 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 8.01-7.95 (m, 3H), 7.90 (td,J=7.5, 1.4 Hz, 1H), 7.87-7.83 (m, 2H), 7.81 (dd, J=8.3, 1.5 Hz, 1H),7.71 (s, 1H), 6.90 (d, J=9.0 Hz, 1H), 4.66 (d, J=5.5 Hz, 2H), 3.61-3.57(m, 4H), 3.45-3.40 (m, 4H), 1.42 (s, 9H); LC-MS: 96.01%; 661.1 (M⁺+1)(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.34 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity):95.67%; (column; X-select CSH-C18 (150×4.6 mm, 3.5 μm); RT 8.38 min.0.05% TFA (Aq)+5% ACN: ACN+5% 0.05% TFA (Aq): 1.0 mL/min, Diluent:ACN:water).

Synthesis of 11-oxo-N-((2-(6-(piperazin-1-yl) pyridin-3-yl)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11019)

To a stirring solution of 11019-A (50 mg, 0.075 mmol) in CH₂Cl₂ (5 mL)was added 4 N HCl in 1, 4-dioxane (5 mL) under argon atmosphere at 0°C.; warmed to RT and stirred for 4 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The crude washed with CH₂Cl₂: n-hexane (1:1, 10 mL) and lyophilized for12 h to afford compound 11019 (40 mg; HCl salt) as an off-white solid.TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.53(s, 1H), 9.49 (t, J=5.7 Hz, 1H), 9.09 (br s, 2H), 8.64 (d, J=2.5 Hz,1H), 8.07-8.01 (m, 2H), 8.00-7.95 (m, 2H), 7.90 (td, J=7.5, 1.5 Hz, 1H),7.88-7.83 (m, 3H), 7.73 (s, 1H), 7.01 (d, J=9.0 Hz, 1H), 4.66 (d, J=5.5Hz, 2H), 3.86-3.80 (m, 4H), 3.21-3.14 (m, 4H); LC-MS: 95.23%; 561.1(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.74 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min). HPLC(purity): 96.14%; (column; X-select CSH-C18 (150×4.6 mm, 3.5 μm); RT5.46 min. 0.05% TFA (Aq)+5% ACN: ACN+5% 0.05% TFA (Aq): 1.0 mL/min,Diluent: ACN:water).

Synthesis of 11016 & 11016-A

Synthesis of tert-butyl 4-(4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) benzoyl) piperazine-1-carboxylate (11016-A)

To a stirring solution of 1585 (300 mg, 0.57 mmol) in DMF (10 mL) underinert atmosphere were added EDCI.HCl (166 mg, 0.86 mmol), HOBt (117 mg,0.86 mmol), tert-butyl piperazine-1-carboxylate 664 (119 mg, 0.63 mmol)and diisopropylethylamine (0.28 mL, 1.98 mmol) at 0° C.; warmed to RTand stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(100 mL) and extracted with EtOAc (2×100 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silicagelcolumn chromatography using 3-4% MeOH/CH₂Cl₂ to afford 11016-A (150 mg,37%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.6); ¹H NMR(DMSO-d₆, 400 MHz): δ 11.52 (br s, 1H), 9.49 (t, J=5.8 Hz, 1H), 8.06 (d,J=8.2 Hz, 1H), 8.02-7.92 (m, 4H), 7.91-7.80 (m, 5H), 7.51 (d, J=8.4 Hz,2H), 4.70 (br d, J=5.6 Hz, 2H), 3.66-3.30 (m, 8H), 1.40 (s, 9H); LC-MS:97.25%; 686.1 (M−1)⁺; (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT2.88 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8mL/min); HPLC (purity): 97.43%; (column; X-Select CSH-C-18 (150×4.6 mm,3.5 μm); RT 10.12 min. 5 mM NH₄OAc: ACN; 1.0 mL/min, Diluent:DMSO:ACN:water).

Synthesis of 11-oxo-N-((2-(4-(piperazine-1-carbonyl)phenyl)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11016)

To a stirring solution of 11016-A (100 mg, 0.19 mmol) in CH₂Cl₂ (10 mL)was added 4 N HCl in 1, 4-dioxane (0.5 mL) under inert atmosphere at 0°C.; warmed to RT and stirred for 3 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The crude washed with diethyl ether (5 mL) and dried in vacuo to afford11016 (80 mg; 66% HCl salt) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.50 (s, 1H), 9.49 (t, J=5.8Hz, 1H), 8.94 (br s, 2H), 8.04 (d, J=8.3 Hz, 1H), 7.98-7.92 (m, 4H),7.90-7.78 (m, 5H), 7.54 (d, J=8.5 Hz, 2H), 4.68 (d, J=5.6 Hz, 2H),3.85-3.49 (m, 4H), 3.18-3.10 (m, 4H); LC-MS: 98.26%; 588.1 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.73 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):98.88%; (column; X-Select CSH-C-18 (150×4.6 mm, 3.5 μm); RT 5.61 min.ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0 mL/min, Diluent:DMSO:ACN:water).

Synthesis of 1585

Synthesis of 4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b, f] [1,4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) benzoic acid (1585)

To a stirring solution of compound 648 (80 mg, 0.15 mmol) in THF:H₂O(5:1, 6 mL) was added lithium hydroxide monohydrate (19 mg, 0.45 mmol)at 0° C.; warmed to RT and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, volatiles were removed invacuo. The crude was washed with EtOAc (2×10 mL). The obtained solid wasdissolved in water (20 mL) and pH was adjusted to ˜2 using 2 N HCl. Theprecipitated solid was filtered, washed with water (20 mL), n-pentane(50 mL) and dried in vacuo to afford 1585 (60 mg, 77%) as an off-whitesolid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ13.18 (br s, 1H), 11.52 (s, 1H), 9.51 (t, J=5.6 Hz, 1H), 8.09-7.95 (m,7H), 7.93-7.80 (m, 5H), 4.71 (d, J=5.8 Hz, 2H); LC-MS: 92.54%; 519.9(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.22 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC(purity): 93.48%; (column; Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT 7.41min. ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0 mL/min).

Preparation

1585 was synthesized as mentioned above and converted to final productsas using commercially available amines employing typical procedure C andthe results are captured in the Table 3:

Typical Procedure C:

To a stirring solution of 1585 (200 mg, 0.38 mmol) in DMF (5 mL) underinert atmosphere were added EDCI.HCl (110 mg, 0.57 mmol), HOBt (77 mg,0.57 mmol), and diisopropylethylamine (0.20 mL, 1.15 mmol) at 0° C. andstirred for 10 min; added compound 240 (2 M sol. in THF, 0.1 mL, 1.15mmol) at the same temperature; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo to obtain the crude. The crude waseither directly dried in vacuo or triturated or purified through silicagel column chromatography to afford the desired compound.

Commercial Amines Used in Preparation:

TABLE 3 Synthesis from 1585 using various amines Proce- dure, Ex-Interme- Rx. Mass am- diate, Yield Spec. Mass Spec. ple Structure amine(%) Found Calculated ¹H-NMR 1943

C, 1 585, 240 59 533.1 (M⁺ + 1); 532 for C₂₆H₂₀N₄O₅S₂ ¹H NMR (DMSO- d₆,400 MHz): δ 11.52 (br s, 1H), 9.50 (br t, J = 5.7 Hz, 1H), 8.52 (q, J =4.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.02-7.94 (m, 4H), 7.93-7.89 (m,3H), 7.89-7.81 (m, 4H), 4.71 (br d, J = 5.6 Hz, 2H), 2.79 (d, J = 4.5Hz, 3H); 1944

C 1 585, 243 71 547.1 (M⁺ + 1); 546 for C₂₇H₂₂N₄O₅S₂ ¹H NMR (DMSO- d₆,400 MHz): δ 11.52 (s, 1H), 9.49 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 8.2Hz, 1H), 8.01-7.95 (m, 2H), 7.95-7.80 (m, 7H), 7.49 (d, J = 8.2 Hz, 2H),4.70 (d, J = 5.6 Hz, 2H), 3.04-2.82 (m, 6H); 1947

C^(a) 1 585, 469 41 575.1 (M⁺ + 1); 574 for C₂₉H₂₆N₄O₅S₂ ¹H NMR (DMSO-d₆, 500 MHz): δ 11.51 (br s, 1H), 9.48 (br t, J = 5.6 Hz, 1H), 8.05 (d,J = 8.1 Hz, 1H), 7.99-7.94 (m, 2H), 7.93-7.79 (m, 10H), 4.69 (br d, J =5.8 Hz, 2H), 1.37 (s, 9H); 1949

C, 1 585, 667 67 559.1 (M⁺ + 1); 558 for C₂₈H₂₂N₄O₅S₂ ¹H NMR (DMSO- d₆,400 MHz): δ 11.52 (br s, 1H), 9.49 (br t, J = 5.4 Hz, 1H), 8.52 (br d, J= 3.5 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 8.02-7.76 (m, 11H), 4.70 (br d,J = 5.5 Hz, 2H), 2.93-2.78 (m, 1H), 0.74-0.52 (m, 4H); C^(a): Reactiontime 18 h

Synthesis of 11017 & 11017-A

Synthesis of tert-butyl (2-(4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f][1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) benzamido) ethyl)carbamate (11017-A)

To a stirring solution of 1585 (300 mg, 0.57 mmol) in DMF (10 mL) underinert atmosphere were added EDCI.HCl (166 mg, 0.86 mmol), HOBt (117 mg,0.86 mmol), tert-butyl (2-aminoethyl) carbamate 669 (102 mg, 0.63 mmol)and diisopropylethylamine (0.28 mL, 1.98 mmol) at 0° C.; warmed to RTand stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(100 mL) and extracted with EtOAc (2×100 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silicagelcolumn chromatography using 3-4% MeOH/CH₂Cl₂ and triturated with 5%MeOH/CH₂Cl₂ (2 mL) and n-pentane (5 mL) and crystallized using N-methylpyrrolidinone: H₂O (10 mL) to afford 11017-A (150 mg, 39%) as anoff-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f). 0.6); ¹H NMR (DMSO-d₆, 400MHz): δ 11.52 (br s, 1H), 9.50 (br t, J=5.8 Hz, 1H), 8.54 (br t, J=4.9Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 8.02-7.80 (m, 11H), 6.90 (br t, J=5.3Hz, 1H), 4.71 (br d, J=5.5 Hz, 2H), 3.31-3.27 (m, 2H), 3.15-3.05 (m,2H), 1.37 (s, 9H); LC-MS: 99.83%; 660.1 (M−1)⁺; (column; Kinetex EVOC-18 (50×3.0 mm, 2.6 um); RT 2.67 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5%2.5 mM Aq.NH₄OOCH, 0.8 mL/min); HPLC (purity): 99.17%; (column; X-SelectCSH-C-18 (150×4.6 mm, 3.5 μm); RT 8.58 min. 0.05% TFA (Aq)+5% ACN:ACN+5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: DMSO:ACN).

Synthesis of N-((2-(4-((2-aminoethyl) carbamoyl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11017)

To a stirring solution of 11017-A (100 mg, 0.15 mmol) in CH₂Cl₂ (10 mL)was added 4 N HCl in 1, 4-dioxane (0.5 mL) under inert atmosphere at 0°C.; warmed to RT and stirred for 3 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The crude washed with diethyl ether (5 mL) and dried in vacuo to afford11017 (80 mg; 88% HCl salt) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.53 (s, 1H), 9.53 (t, J=5.8Hz, 1H), 8.74 (t, J=5.5 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.03-7.95 (m,6H), 7.93-7.81 (m, 8H), 4.71 (br d, J=5.6 Hz, 2H), 3.55-3.49 (m, 2H),3.02-2.96 (m, 2H); LC-MS: 98.39%; 562.1 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.74 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 99.17%; (column;X-Select CSH-C-18 (150×4.6 mm, 3.5 μm); RT 8.58 min. 0.05% TFA (Aq)+5%ACN: ACN+5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN: DMSO: MeOH).

Synthesis of 11018 & 11018-A

Synthesis of 11-oxo-N-((2-(4-(piperazin-1-yl) phenyl) thiazol-5-yl)methyl)-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5,5-dioxide hydrochloride (11018)

To a stirring solution of 11018-A (100 mg, 0.15 mmol) in CH₂Cl₂ (10 mL)was added 4 N HCl in 1, 4-dioxane (1 mL) under argon atmosphere at 0°C.; warmed to RT and stirred for 2 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The crude washed with EtOAc (2×5 mL) and dried in vacuo to afford 1 1018(75 mg, 88%; HCl salt) as yellow solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f).0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.53 (s, 1H), 9.49 (t, J=5.8 Hz,1H), 9.18 (br s, 2H), 8.05 (d, J=8.3 Hz, 1H), 7.98 (td, J=7.4, 1.1 Hz,2H), 7.93-7.81 (m, 4H), 7.76 (d, J=8.9 Hz, 2H), 7.70 (s, 1H), 7.05 (d,J=8.9 Hz, 2H), 4.65 (br d, J=5.6 Hz, 2H), 3.51-3.44 (m, 4H), 3.24-3.17(m, 4H); LC-MS: 98.17%; 560.1 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 1.77 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min). HPLC (purity): 97.26%; (column; X-select CSH C-18(150×4.6 mm, 3.5 μm); RT 6.21 min. 0.05% TFA+5% ACN: ACN+0.05% TFA+5%;1.0 mL/min; Diluent: ACN:water).

Synthesis of 1581

Synthesis of ethyl 2-(4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo[b, f] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy)acetate (670)

To a stirring solution of compound 92 (150 mg, 0.49 mmol) in DMF (10 mL)under inert atmosphere were added EDCI.HCl (142 mg, 0.29 mmol), HOBt(100 mg, 0.74 mmol), ethyl 2-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)acetate hydrochloride 639 (195 mg, 0.59 mmol) and diisopropylethylamine(0.45 mL, 2.47 mmol) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was poured into ice-cold water (50 mL) and extractedwith EtOAc (3×150 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using 3%MeOH/CH₂Cl₂ to afford compound 670 (110 mg, 39%) as white solid. TLC: 7%MeOH/CH₂Cl₂ (R_(f). 0.4); ¹H NMR (DMSO-d₆, 500 MHz): δ 11.51 (s, 1H),9.45 (t, J=5.8 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 8.00-7.95 (m, 2H), 7.90(td, J=7.4, 1.3 Hz, 1H), 7.87-7.85 (m, 2H), 7.84-7.79 (m, 3H), 7.73 (s,1H), 7.02 (d, J=9.0 Hz, 2H), 4.85 (s, 2H), 4.67 (d, J=5.8 Hz, 2H), 4.17(q, J=6.9 Hz, 2H), 1.21 (t, J=7.1 Hz, 3H).

Synthesis of 2-(4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b, f][1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) aceticacid (1581)

To a stirring solution of compound 670 (80 mg, 0.13 mmol) in THF:H₂O(4:1, 10 mL) was added lithium hydroxide monohydrate (18 mg, 0.42 mmol)at RT and stirred for 4 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. The pHof the residue was acidified with 2 N HCl to ˜6. The precipitated solidwas filtered triturated with 20% EtOAc/hexanes (10 mL) and dried invacuo to afford 1581 (60 mg, 79%) as an off-white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ 11.51 (s, 1H),9.46 (t, J=5.6 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.97 (t, J=8.4 Hz, 2H),7.89 (t, J=7.1 Hz, 1H), 7.86-7.78 (m, 5H), 7.72 (s, 1H), 6.99 (d, J=8.7Hz, 2H), 4.73 (s, 2H), 4.65 (d, J=5.5 Hz, 2H); LC-MS: 100%; 549.9(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.06 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC(purity): 99.71%; (column; Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT 7.22min. ACN: 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN:water).

Synthesis of 1995 and 1995-A

Synthesis of tert-butyl 3-(((methylsulfonyl) oxy) methyl)azetidine-1-carboxylate (1595)

To a stirring solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate 671 (500 mg, 2.67 mmol) in CH₂Cl₂ (10 mL) underinert atmosphere were added triethylamine (0.77 mL, 5.34 mmol),methanesulfonyl chloride (0.24 mL, 2.94 mmol) at 0° C.; warmed to RT andstirred for 2 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with CH₂Cl₂ (75 mL),washed with water (2×50 mL) The organic extract was dried over sodiumsulfate, filtered and concentrated in vacuo to afford crude compound 672(580 mg) as sticky solid. TLC: 60% EtOAc/hexanes (R_(f): 0.4); ¹H NMR(DMSO-d₆, 500 MHz): δ 4.34 (d, J=6.4 Hz, 2H), 3.95-3.87 (m, 2H),3.65-3.56 (m, 2H), 3.21 (s, 3H), 2.95-2.84 (m, 1H), 1.37 (s, 9H);

Synthesis of tert-butyl 3-((4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) methyl) azetidine-1-carboxylate (1995-A)

To a stirring solution of N-((2-(4-hydroxyphenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide 1595 (600 mg, 1.22 mmol) in DMF(100 mL) under inert atmosphere were added 4-bromo-1H-pyrazole 672 (5.92g, 40.29 mmol), cesium carbonate (39.4 g, 120.96 mmol) at RT; heated to80° C. and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted withice-cold water (500 mL) and extracted with EtOAc (2×200 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silicagel column chromatography using 30% EtOAc/hexanes toafford 1995-A (4.1 g, 29%) as an off-white solid. TLC: 30% EtOAc/hexanes(R_(f): 0.3). ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.46 (t, J=5.7Hz, 1H), 8.59 (d, J=5.5 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.98 (t, J=7.5Hz, 1H), 7.93-7.79 (m, 5H), 7.73 (s, 1H), 7.07 (d, J=8.7 Hz, 2H), 4.66(d, J=5.3 Hz, 2H), 4.18 (d, J=5.3 Hz, 2H), 4.12-4.04 (m, 2H), 3.93-3.81(m, 2H), 3.27-3.16 (m, 1H); LC-MS: 97.70%; 659.1 (M−1)⁺; (column;Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 1.27 min. 2.5 mM Aq. NH₄OOCH+5%ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min); HPLC (purity): 99.67%;(column; X select CSH C-18 (150×4.6 mm, 3.5 nm); RT 10.33 min. 0.05%TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent: ACN:water).

Synthesis of N-((2-(4-(azetidin-3-ylmethoxy) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide TFA salt (1995)

To stirred solution of tert-butyl 3-((4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) methyl) azetidine-1-carboxylate (1995-A) (200 mg,0.30 mmol) in CH₂Cl under inert atmosphere was added trifluoroaceticacid (0.11 mL, 1.51 mmol) at 0° C.; warmed to RT and stirred for 24 h.The reaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo to obtain the crude, which wastriturated with EtOAc (2×10 mL) and dried in vacuo to afford 1995 (90mg, 43%, TFA salt) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f):0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.46 (t, J=5.7 Hz,1H), 8.60 (br s, 2H), 8.06 (d, J=8.1 Hz, 1H), 7.98 (t, J=7.5 Hz, 2H),7.93-7.79 (m, 6H), 7.73 (s, 1H), 7.07 (d, J=8.7 Hz, 2H), 4.66 (d, J=5.3Hz, 2H), 4.18 (d, J=5.3 Hz, 2H), 4.12-4.04 (m, 2H), 3.93-3.81 (m, 2H),3.27-3.16 (m, 1H); LC-MS: 96.93%; 491.0 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.80 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 95.81%; (column;X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 9.23 min. ACN+5 mM NH₄OAc:ACN; 1.0 mL/min, Diluent: DMSO:ACN:water).

Synthesis of 1997

Synthesis of tert-butyl 3-(hydroxymethyl) piperidine-1-carboxylate (674)

To a stirring solution of piperidin-3-ylmethanol 673 (1 g, 8.69 mmol) inCH₂Cl₂ (10 mL) under argon atmosphere were added triethylamine (3.66 mL,26.08 mmol), Boc-anhydride (2.39 mL, 10.43 mmol) at 0° C.; warmed to RTand stirred for 5 h. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was diluted with water (30 mL) andextracted with CH₂Cl₂ (2×30 mL). The combined organic extracts werewashed with water (40 mL) and brine (40 mL); dried over sodium sulfate,filtered and concentrated in vacuo to afford compound 674 (1.6 g, 86%)as pale yellow liquid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H-NMR(DMSO-d₆, 400 MHz): δ 4.49 (t, J=5.3 Hz, 1H), 4.04-3.87 (m, 1H),3.81-3.76 (m, 1H), 3.30-3.25 (m, 1H), 3.20-3.14 (m, 1H), 2.77-2.61 (m,1H), 1.75-1.62 (m, 1H), 1.62-1.53 (m, 1H), 1.51-1.42 (m, 1H), 1.39 (s,9H), 1.36-1.18 (m, 1H), 1.14-1.01 (m, 1H);

Synthesis of tert-butyl 3-(((methylsulfonyl) oxy) methyl)piperidine-1-carboxylate (675)

To a stirring solution of compound 674 (500 mg, 2.487 mmol) in CH₂Cl₂(15 mL) under inert atmosphere were added triethylamine (1.04 mL, 7.46mmol), methanesulfonyl chloride (0.24 mL, 3.73 mmol) at 0° C.; warmed toRT and stirred for 3 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(25 mL) and extracted with CH₂Cl₂ (2×30 mL). The combined organicextracts were washed with water (20 mL) and brine (20 mL); dried oversodium sulfate, filtered and concentrated in vacuo to afford crudecompound 675 (600 mg crude) as pale yellow liquid. TLC: 30%EtOAc/hexanes (R_(f): 0.5); ¹H-NMR (DMSO-d₆, 400 MHz): δ 4.13-4.02 (m,2H), 3.73-3.69 (m, 1H), 3.17 (s, 3H), 2.92-2.78 (m, 2H), 1.85-1.67 (m,3H), 1.65-1.55 (m, 1H), 1.39 (s, 9H), 1.36-1.12 (m, 2H);

Synthesis of tert-butyl 3-((4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) methyl) piperidine-1-carboxylate (676)

To a stirring solution of N-((2-(4-hydroxyphenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide 1 595 (400 mg, 0.81 mmol) in DMF(8 mL) were added cesium carbonate (796 mg, 2.44 mmol), compound 675(272 mg, 0.97 mmol) under argon atmosphere at RT; heated to 70° C. in asealed tube and stirred for 16 h. The reaction was monitored by TLC;after completion, the reaction mixture was diluted with water (30 mL)and extracted with EtOAc (2×40 mL). The combined organic extracts werewashed with water (40 mL) and brine (40 mL); dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 3% MeOH/CH₂Cl₂to afford compound 676 (50 mg, 9%) as pale yellow solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.6); ¹H NMR (400 MHz, DMSO-d₆): δ 11.51 (s, 1H),9.45 (t, J=5.7 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 8.00-7.95 (m, 2H),7.93-7.84 (m, 3H), 7.84-7.78 (m, 3H), 7.72 (s, 1H), 7.02 (d, J=8.9 Hz,2H), 4.66 (d, J=5.6 Hz, 2H), 3.95-3.84 (m, 2H), 3.74-3.60 (m, 1H),2.98-2.82 (m, 2H), 1.93-1.86 (m, 1H), 1.83-1.75 (m, 1H), 1.66-1.59 (m,1H), 1.42-1.29 (m, 12H); LC-MS: 92.11%; 589.1 (M⁺+1) des BOC; (column;Ascentis Express C-18, (50×3.0 mm, 2.7 μm); RT 2.74 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of 11-oxo-N-((2-(4-(piperidin-3-ylmethoxy) phenyl)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1997)

To a stirring solution of compound 675 (38 mg, 0.055 mmol) in CH₂Cl₂ (2mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under argon atmosphere at0° C.; warmed to RT and stirred for 1 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude washed with diethyl ether (5 mL) and dried in vacuo toafford 1997 (20 mg; 58%) as white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f):0.1); ¹H NMR (400 MHz, DMSO-d₆): δ 11.53 (s, 1H), 9.49 (t, J=5.7 Hz,1H), 8.92-8.83 (m, 1H), 8.75-8.63 (m, 1H), 8.06 (d, J=8.2 Hz, 1H),8.01-7.96 (m, 2H), 7.92-7.80 (m, 6H), 7.73 (s, 1H), 7.03 (d, J=8.9 Hz,2H), 4.66 (d, J=5.5 Hz, 2H), 4.04-3.89 (m, 2H), 3.38-3.32 (m, 1H),3.28-3.20 (m, 1H), 2.85-2.71 (m, 2H), 2.28-2.18 (m, 1H), 1.89-1.79 (m,2H), 1.73-1.63 (m, 1H), 1.41-1.28 (m, 1H); LC-MS: 99.93%; 589.1 (M⁺+1);(column; Ascentis Express C-18, (50×3.0 mm, 2.7 μm); RT 1.86 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):97.78%; (column; X select CSH C-18 (150×4.6 mm, 3.5 μm); RT 5.74 min.0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent: ACN:water).

Synthesis of 11137 & 11138

Synthesis of benzyl 4-(hydroxymethyl) piperidine-1-carboxylate (678)

To a stirring solution of piperidin-4-ylmethanol 677 (4 g, 34.72 mmol)in CH₂Cl₂ (100 mL) were added triethylamine (15 mL, 104.17 mmol)followed by benzyl chloroformate (50% in toluene, 13 mL, 38.19 mmol) at0° C. under inert atmosphere. The reaction mixture was gradually warmedto RT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withaqueous saturated sodium bicarbonate solution (40 mL) and extracted withEtOAC (2×40 mL). The combined organic extracts were washed dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through column chromatography using 50%EtOAc/hexanes to afford compound 678 (5 g, 58%) as Pale yellow liquid.TLC: 50% EtOAc/hexanes (R_(f): 0.3); ¹H NMR (500 MHz, DMSO-d₆): δ7.44-7.27 (m, 5H), 5.06 (s, 2H), 4.46 (t, J=5.2 Hz, 1H), 4.03-3.98 (m,2H), 3.24 (t, J=5.8 Hz, 2H), 2.79-2.75 (m, 2H), 1.67-1.62 (m, 2H),1.58-1.50 (m, 1H), 1.05-0.96 (m, 2H); LC-MS: 89.34%; 250.1 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.06 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl 4-(((methylsulfonyl) oxy) methyl)piperidine-1-carboxylate (679)

To a stirring solution of compound 678 (1.25 g, 5.02 mmol) in CH₂Cl₂ (20mL) were added methanesulfonyl chloride (0.5 mL, 6.02 mmol) andtriethylamine (1.08 mL, 7.53 mmol) at 0° C. under inert atmosphere. Thereaction mixture was gradually warmed to RT and stirred for 2 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was poured slowly into aqueous saturated sodiumbicarbonate solution (20 mL) and extracted with EtOAc (2×35 mL). Thecombined organic extracts were washed dried over sodium sulfate,filtered and concentrated in vacuo to afford compound 679 (1.5 g) aspale yellow liquid. This crude material was taken to next step withoutfurther purification. TLC: 50% EtOAc/hexanes (R_(f): 0.8); ¹H NMR (500MHz, DMSO-d₆): δ 7.45-7.26 (m, 5H), 5.07 (s, 2H), 4.11-3.99 (m, 4H),3.17 (s, 3H), 2.89-2.72 (m, 2H), 1.94-1.83 (m, 1H), 1.70-1.66 (m, 2H),1.22-1.05 (m, 2H); LC-MS: 91.59%; 328.0 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.37 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl 4-((4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenoxy) methyl) piperidine-1-carboxylate (680)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (1 g, 3.27 mmol) in DMF (15 mL) were addedcompound 679 (1.17 g, crude) and cesium carbonate (2.66 g, 8.17 mmol) atRT under inert atmosphere. The reaction mixture was heated to 70° C. andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with ice cold water (30mL) and extracted with EtOAc (2×50 mL). The combined organic extractswere washed dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through columnchromatography using 2% MeOH/CH₂Cl₂ to afford compound 680 (1.3 g, 74%)as an off white solid. TLC: 40% EtOAc/hexanes (R_(f): 0.7); ¹H NMR (400MHz, DMSO-d₆): δ 7.80 (d, J=8.8 Hz, 2H), 7.60 (s, 1H), 7.53 (t, J=5.7Hz, 1H), 7.40-7.29 (m, 5H), 7.02 (d, J=8.9 Hz, 2H), 5.08 (s, 2H), 4.31(d, J=5.9 Hz, 2H), 4.09-4.03 (m, 2H), 3.90 (d, J=6.4 Hz, 2H), 2.85-2.79(m, 2H), 2.04-1.92 (m, 1H), 1.82-1.75 (m, 2H), 1.40 (s, 9H), 1.26-1.15(m, 2H); LC-MS: 90.14%; 538.3 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 3.06 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min).

Synthesis of benzyl 4-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy)methyl) piperidine-1-carboxylate hydrochloride (681)

To a stirring solution of compound 680 (1.3 g, 2.42 mmol) in CH₂Cl₂ (15mL) was added 4 N HCl in 1, 4-dioxane (4 mL) at 0° C. under inertatmosphere. The reaction mixture was gradually warmed to RT and stirredfor 2 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo to obtain the crude. Thecrude was triturated with EtOAc (30 mL), diethylether (30 mL) and driedin vacuo to afford compound 681 (1.1 g, HCl salt) as an off white solid.TLC: 40% EtOAc/hexanes (R_(f): 0.1); ¹H NMR (500 MHz, DMSO-d₆): δ 8.64(br s, 3H), 7.91 (s, 1H), 7.85 (d, J=8.7 Hz, 2H), 7.41-7.29 (m, 5H),7.06 (d, J=8.7 Hz, 2H), 5.08 (s, 2H), 4.31 (q, J=5.2 Hz, 2H), 4.08-4.03(m, 2H), 3.91 (d, J=6.4 Hz, 2H), 2.96-2.78 (m, 2H), 2.03-1.92 (m, 1H),1.80-1.76 (m, 2H), 1.27-1.15 (m, 2H); LC-MS: 99.39%; 438.1 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.07 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl 4-((4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo[b, f] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy)methyl) piperidine-1-carboxylate (682)

To a stirring solution of 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide 92 (200 mg, 0.66 mmol) in DMF(15 mL) were added compound 681 (312 mg, 0.66 mmol), EDCI.HCl (189 mg,0.99 mmol), HOBt (135 mg, 0.99 mmol) and diisopropylethylamine (0.6 mL,0.33 mmol) at 0° C. under inert atmosphere. The reaction mixture wasgradually warmed to RT and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasdiluted with ice cold water (20 mL) and extracted with EtOAc (2×30 mL).The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude was purifiedthrough column chromatography using 4% MeOH/CH₂Cl₂ to afford compound682 (310 mg, 65%) as an off white solid. TLC: 6% MeOH/CH₂Cl₂ (R_(f):0.5); ¹H NMR (500 MHz, DMSO-d₆): δ 11.51 (s, 1H), 9.44 (t, J=5.5 Hz,1H), 8.06 (d, J=8.1 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.83 (m, 3H),7.83-7.77 (m, 3H), 7.72 (s, 1H), 7.40-7.30 (m, 5H), 7.01 (d, J=9.3 Hz,2H), 5.07 (s, 2H), 4.66 (d, J=5.8 Hz, 2H), 4.07-4.03 (m, 2H), 3.89 (d,J=6.4 Hz, 2H), 2.93-2.77 (m, 2H), 2.01-1.93 (m, 1H), 1.79-1.75 (m, 2H),1.25-1.15 (m, 2H); LC-MS: 93.17%; 723.2 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.83 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 11-oxo-N-((2-(4-(piperidin-4-ylmethoxy) phenyl)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11137)

To a stirring solution of compound 682 (200 mg, 0.28 mmol) in CH₂Cl₂ (5mL) was added trimethylsilyl iodide (0.04 mL, 0.28 mmol) at 0° C. underinert atmosphere. The reaction mixture was gradually warmed to RT andstirred for 1 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with saturated sodiumbicarbonate solution (20 mL) and extracted with EtOAc (2×30 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough column chromatography using 8% MeOH/CH₂Cl₂ to afford 11137 (83mg, 50%) as an off white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹HNMR (400 MHz, DMSO-d₆): δ 9.45 (t, J=5.6 Hz, 1H), 8.05 (d, J=8.3 Hz,1H), 7.97 (td, J=7.6, 1.1 Hz, 2H), 7.93-7.77 (m, 6H), 7.72 (s, 1H), 7.01(d, J=8.8 Hz, 2H), 4.66 (d, J=5.6 Hz, 2H), 3.85 (d, J=6.3 Hz, 2H),3.03-2.98 (m, 2H), 2.60-2.53 (m, 2H), 1.86-1.84 (m, 1H), 1.74-1.69 (m,2H), 1.27-1.14 (m, 2H); LC-MS: 98.61%; 589.1 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.84 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-((2-(4-((1-methylpiperidin-4-yl) methoxy) phenyl)thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11138)

To a stirring solution of 11-oxo-N-((2-(4-(piperidin-4-ylmethoxy)phenyl) thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide 11137 (75 mg, 0.13 mmol) inmethanol (5 mL) were added paraformaldehyde (19 mg, 0.64 mmol) andsodium cyanoborohydride (39 mg, 0.64 mmol) at 0° C. under inertatmosphere. The reaction mixture was gradually warmed to RT and stirredfor 16 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo. The residue was dilutewith ice cold water (20 mL) and extracted with 10% MeOH/CH₂Cl₂ (2×30mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through column chromatography using 8% MeOH/CH₂Cl₂ to affordN-methylated compound (50 mg) as an off white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.7). This was taken forward for next step.

To a stirring solution of above N-methylated compound (50 mg) in CH₂Cl₂(2 mL) was added 4 N HCl in 1, 4-dioxane (0.5 mL) at 0° C. under inertatmosphere. The reaction mixture was gradually warmed to RT and stirredfor 1 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo to obtain the crude. Thecrude was triturated with EtOAc (10 mL), diethylether (10 mL), followedby preparative HPLC purification to afford 11138 (38 mg, 46%, for twosteps) as an off white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H NMR(400 MHz, DMSO-d₆): δ 11.53 (s, 1H), 9.47 (t, J=5.6 Hz, 1H), 9.29 (br s,1H), 8.06 (d, J=8.2 Hz, 1H), 8.00-7.95 (m, 2H), 7.92-7.79 (m, 6H), 7.73(s, 1H), 7.02 (d, J=8.9 Hz, 2H), 4.66 (d, J=5.5 Hz, 2H), 3.92 (d, J=5.6Hz, 2H), 3.48-3.43 (m, 2H), 3.29-3.12 (m, 1H), 3.02-2.91 (m, 2H), 2.76(d, J=4.6 Hz, 3H), 2.02-1.94 (m, 2H), 1.56-1.43 (m, 2H); LC-MS: 99.63%;603.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT1.85 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);HPLC (purity): 99.37%; (column; X-Select CSH-C-18 (150×4.6 mm, 3.5 μm);RT 6.14 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent:ACN:H₂O).

Synthesis of 11104-A & 11104

Synthesis of tert-butyl (R)-2-(hydroxymethyl) pyrrolidine-1-carboxylate(684)

To a stirring solution of (R)-pyrrolidin-2-ylmethanol 683 (1 g, 9.88mmol) in CH₂Cl₂ (20 mL) under inert atmosphere was added triethylamine(1.57 mL, 10.89 mmol) at 0° C., followed by addition of Boc-anhydride(2.5 mL, 10.89 mmol) at the same temperature; warmed to RT and stirredfor 4 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with water (20 mL), dilutedwith 1 N HCl (10 mL). The aqueous layer was concentrated in vacuo toafford crude compound 684 (1.9 g) as colorless syrup which was carriedforward for next step without further purification. TLC: 20%EtOAc/hexanes (R_(f). 0.4); ¹H NMR (CDCl₃, 400 MHz): δ 4.74 (br d, J=5.5Hz, 1H), 4.01-3.98 (m, 1H), 3.73-3.56 (m, 2H), 3.54-3.44 (m, 1H),3.36-3.33 (m, 1H), 2.09-1.97 (m, 1H), 1.89-1.84 (m, 2H), 1.50 (s, 9H);

Synthesis of tert-butyl (R)-2-(((methylsulfonyl) oxy) methyl)pyrrolidine-1-carboxylate (685)

To a stirring solution of compound 684 (1 g, crude) in CH₂Cl₂ (20 mL)under inert atmosphere were added triethylamine (1.40 mL, 9.95 mmol),methanesulfonyl chloride (0.68 mL, 8.45 mmol) at 0° C.; warmed to RT andstirred for 3 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with water (50 mL) andextracted with CH₂Cl₂ (2×50 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silicagel columnchromatography using 20% EtOAc/hexanes to afford compound 685 (1.05 g,38%, over 2 steps) as colorless liquid. TLC: 20% EtOAc/hexanes (R_(f):0.5); ¹H NMR (CDCl₃, 400 MHz): δ 4.39-4.22 (m, 1.6H), 4.16-3.98 (m,1.4H), 3.53-3.29 (m, 2H), 3.02 (s, 3H), 2.12-1.81 (m, 4H), 1.60 (s, 9H);

Synthesis of tert-butyl (R)-2-((4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) methyl) pyrrolidine-1-carboxylate (11104-A)

To a stirring solution of N-((2-(4-hydroxyphenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide 1595 (1 g, 2.03 mmol) in DMF (3mL) under inert atmosphere were added ter t-butyl(R)-2-(((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate 685 (568mg, 2.03 mmol), cesium carbonate (1.99 g, 6.10 mmol) at RT; heated to80° C. and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(50 mL) and extracted with EtOAc (2×25 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silicagelcolumn chromatography using 3% MeOH/CH₂Cl₂ to afford 11104-A (460 mg,35%) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.6); ¹H NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.44 (t, J=5.6 Hz, 1H), 8.05 (d,J=8.2 Hz, 1H), 8.01-7.94 (m, 2H), 7.93-7.77 (m, 6H), 7.72 (s, 1H), 7.05(d, J=8.9 Hz, 2H), 4.66 (d, J=5.6 Hz, 2H), 4.14-3.91 (m, 3H), 3.29-3.25(m, 2H), 2.05-1.75 (m, 4H), 1.40 (s, 9H); LC-MS: 94.40%; 619.1(M-^(t)Bu)⁺ (Column; X-select CSH C-18 (150×3.0 mm, 2.7 μm); RT 2.70min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.0 mL/min); HPLC(purity): 96.20%; (column; X-Select CSH-C-18 (150×4.6 mm, 3.5 μm); RT10.64 min. 0.05% TFA (Aq)+5% ACN: ACN+5% 0.05% TFA (Aq); 1.0 mL/min,Diluent: ACN:H₂O).

Synthesis of (R)-11-oxo-N-((2-(4-(pyrrolidin-2-ylmethoxy) phenyl)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11104)

To a stirring solution of 11104-A (450 mg, 0.66 mmol) in CH₂Cl₂ (10 mL)under inert atmosphere was added 4 N HCl in 1, 4-dioxane (4 mL) at 0°C.; warmed to RT and stirred for 4 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The crude washed with diethyl ether (5 mL), EtOAc (5 mL), n-pentane (5mL) and dried in vacuo to afford 1 1104 (280 mg, 69%; HCl salt) as anoff-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.0; ¹H NMR (DMSO-d₆, 400MHz): δ 11.53 (s, 1H), 9.48 (t, J=5.8 Hz, 1H), 9.38-9.28 (m, 1H),8.91-8.76 (m, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.01-7.96 (m, 2H), 7.93-7.80(m, 6H), 7.74 (s, 1H), 7.08 (d, J=8.9 Hz, 2H), 4.66 (d, J=5.6 Hz, 2H),4.32 (dd, J=3.5, 10.7 Hz, 1H), 4.16 (dd, J=8.5, 10.6 Hz, 1H), 3.99-3.87(m, 1H), 3.27-3.16 (m, 2H), 2.18-2.09 (m, 1H), 2.04-1.86 (m, 2H),1.79-1.70 (m, 1H); LC-MS: 94.56%; 575.1 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.82 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 95.85%; (column;X-Select CSH-C-18 (150×4.6 mm, 3.5 μm); RT 5.86 min. 0.05% TFA (Aq)+5%ACN: ACN+5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN:H₂O).

Synthesis of 11131

Synthesis of (R)—N-((2-(4-((1-methylpyrrolidin-2-yl) methoxy) phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5,5-dioxide (11131)

To a stirring solution of 11104 (120 mg, 0.19 mmol) in MeOH (10 mL)under inert atmosphere were added paraformaldehyde (29 mg, 0.98 mmol)and sodium cyanoborohydride (62 mg, 0.98 mmol) at RT and stirred for 6h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was quenched with ice-cold water (10 mL) andextracted with CH₂Cl₂ (3×15 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 4% MeOH/CH₂Cl₂ and 2 mL aqueous ammonia to obtainsemi solid, which was washed further with diethyl ether and hexane anddried in vacuo to afford 11131 (100 mg, 63%) as an off whit solid. TLC:10% MeOH/CH₂Cl₂ (R_(f): 0.6); ¹H NMR (DMSO-d₆, 400 MHz): δ 11.51 (br s,1H), 9.44 (t, J=5.7 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.98 (dd J=7.5, 1.0Hz, 2H), 7.93-7.76 (m, 6H), 7.72 (m, 1H), 7.02 (d, J=8.9 Hz, 1H), 4.66(br d, J=5.6 Hz, 2H), 4.01 (dd, J=5.3, 9.6 Hz, 1H), 3.87 (dd, J=6.0, 9.6Hz, 1H), 2.99-2.92 (m, 1H), 2.70-2.65 (m, 1H), 2.62-2.54 (m, 1H),2.25-2.14 (m, 1H), 2.02-1.90 (m, 1H), 1.73-1.64 (m, 2H), 1.63-1.53 (m,1H); LC-MS: 97.99%; 589.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0mm, 2.7 μm); RT 1.67 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min). HPLC (purity): 98.46%; (column; X-Select CSH-C-18 (150×4.6mm, 3.5 μm); RT 5.90 min. 0.05% TFA (Aq)+5% ACN: ACN+5% 0.05% TFA (Aq);1.0 mL/min, Diluent: ACN:H₂O).

Synthesis of 11029

Synthesis of tert-butyl (S)-2-(hydroxymethyl) pyrrolidine-1-carboxylate(687)

To a stirring solution of (S)-pyrrolidin-2-ylmethanol 686 (1 g, 9.88mmol) in CH₂Cl₂ (20 mL) under inert atmosphere was added triethylamine(1.57 mL, 10.89 mmol) at 0° C., followed by addition of Boc-anhydride(2.5 mL, 10.89 mmol) at the same temperature; warmed to RT and stirredfor 6 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with water (20 mL), dilutedwith 1 N HCl (20 mL). The aqueous layer was concentrated in vacuo toafford crude compound 687 (1.9 g) as colorless syrup which was carriedforward for next step without further purification. TLC: 20%EtOAc/hexanes (R_(f). 0.4); ¹H-NMR (CDCl₃, 500 MHz): δ 4.74-4.70 (m,1H), 3.97 (d, J=5.2 Hz, 1H), 3.68-3.54 (m, 2H), 3.49-3.42 (m, 1H),3.36-3.28 (m, 1H), 2.07-1.94 (m, 1H), 1.90-1.74 (m, 2H), 1.47 (s, 9H);

Synthesis of tert-butyl (S)-2-(((methylsulfonyl) oxy) methyl)pyrrolidine-1-carboxylate (688)

To a stirring solution of compound 687 (1 g, crude) in CH₂Cl₂ (20 mL)under inert atmosphere were added triethylamine (1.40 mL, 9.95 mmol),methanesulfonyl chloride (0.68 mL, 8.45 mmol) at 0° C.; warmed to RT andstirred for 3 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with water (50 mL) andextracted with CH₂Cl₂ (2×50 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to affordcompound 688 (570 mg, crude) as colorless liquid. TLC: 20% EtOAc/hexanes(R_(f): 0.5); The crude was carried forward for next step withoutfurther purification.

Synthesis of tert-butyl (S)-2-((4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) methyl) pyrrolidine-1-carboxylate (689)

To a stirring solution of N-((2-(4-hydroxyphenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide 1 595 (1 g, 2.03 mmol) in DMF (20mL) under inert atmosphere were added tert-butyl(S)-2-(((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate 688 (568mg, crude), cesium carbonate (1.99 g, 6.10 mmol) at RT and stirred for16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with water (50 mL) andextracted with EtOAc (2×30 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silicagel column chromatographyusing 2% MeOH/CH₂Cl₂ to afford compound 689 (210 mg, 16%) as yellowsolid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); LC-MS: 94.40%; 619.1 (M⁺+1)(−^(t)Bu) (Column; X-select CSH C-18 (150×3.0 mm, 2.7 μm); RT 2.70 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.0 mL/min). ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.44 (t, J=5.8 Hz, 1H), 8.05 (d,J=8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.77 (m, 6H), 7.72 (s, 1H), 7.05(d, J=8.9 Hz, 2H), 4.66 (d, J=5.6 Hz, 2H), 4.16-3.88 (m, 3H), 3.29-3.25(m, 2H), 2.05-1.75 (m, 4H), 1.40 (s, 9H); LC-MS: 93.14%; 675.2 (M⁺+1);(column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 3.43 min. 2.5 mM Aq.NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of (S)-11-oxo-N-((2-(4-(pyrrolidin-2-ylmethoxy) phenyl)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11029)

To a stirring solution of compound 689 (200 mg, 0.29 mmol) in CH₂Cl₂ (10mL) was added 4 N HCl in 1, 4-dioxane (10 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was washed with diethyl ether (5 mL), EtOAc (5 mL),hexane (5 mL) and dried in vacuo to afford 11029 (130 mg, HCl salt) asan off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H NMR (DMSO-d₆,400 MHz): δ 11.53 (s, 1H), 9.48 (t, J=5.8 Hz, 1H), 9.42-9.28 (m, 1H),8.94-8.73 (m, 1H), 8.06 (d, J=8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.80(m, 6H), 7.74 (s, 1H), 7.08 (d, J=8.9 Hz, 2H), 4.66 (d, J=5.6 Hz, 2H),4.32 (dd, J=10.7, 3.5 Hz, 1H), 4.17 (dd, J=10.5, 8.4 Hz, 1H), 3.97-3.89(m, 1H), 3.28-3.17 (m, 2H), 2.16-2.08 (m, 1H), 2.05-1.95 (m, 1H),1.95-1.84 (m, 1H), 1.80-1.68 (m, 1H); LC-MS: 93.84%; 575.1 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.82 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity):93.14%; (column; X-select CSH-C18 (150×4.6 mm, 3.5 μm); RT 5.83 min.0.05% TFA (Aq)+5% ACN: ACN+5% 0.05% TFA (Aq); 1.0 mL/min, Diluent:DMSO:ACN:water).

Synthesis of 11135

Synthesis of (S)—N-((2-(4-((1-methylpyrrolidin-2-yl) methoxy) phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5,5-dioxide (11135)

To a stirring solution of 11029 (90 mg, 0.14 mmol) in MeOH (5 mL) underinert atmosphere were added paraformaldehyde (22 mg, 0.73 mmol) andsodium cyanoborohydride (46 mg, 0.73 mmol) at RT and stirred for 16 h.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was quenched with ice-cold water (10 mL) and extractedwith CH₂Cl₂ (3×20 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using 5%MeOH/CH₂Cl₂ and 2 mL aqueous ammonia to afford 11135 (73 mg, 83%) as anoff white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.6); 41 NMR (DMSO-d₆, 400MHz): δ 11.51 (br s, 1H), 9.45 (t, J=5.7 Hz, 1H), 8.06 (d, J=8.3 Hz,1H), 8.02-7.95 (m, 2H), 7.92-7.78 (m, 6H), 7.72 (s, 1H), 7.02 (d, J=8.7Hz, 2H), 4.66 (d, J=5.6 Hz, 2H), 4.02 (dd, J=9.6, 5.5 Hz, 1H), 3.94-3.85(m, 1H), 3.01-2.96 (m, 1H), 2.65-2.56 (m, 1H), 2.38 (br s, 3H),2.27-2.16 (m, 1H), 2.01-1.92 (m, 1H), 1.76-1.55 (m, 3H); LC-MS: 96.81%;589.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT1.83 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);HPLC (purity): 97.00%; (column; X-select CSH-C18 (150×4.6 mm, 3.5 μm);RT 5.98 min. 0.05% TFA (Aq)+5% ACN: ACN+5% 0.05% TFA (Aq); 1.0 mL/min,Diluent: DMSO:ACN:water).

Synthesis of 11139

Synthesis of (S)-pyrrolidin-3-ylmethanol TFA Salt (691)

To a stirring solution of tert-butyl (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate 690 (2 g, 14.90 mmol) in CH₂Cl₂ (30 mL) underinert atmosphere was added trifluoroacetic acid (30 mL) at 0° C. andstirred for 30 min. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was diluted with water (100 mL)and extracted with CH₂Cl₂ (2×75 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to affordcrude compound 691 (2 g) as yellow syrup. TLC: 20% EtOAc/hexanes (R_(f):0.2).

Synthesis of benzyl (S)-3-(hydroxymethyl) pyrrolidine-1-carboxylate(692)

To a stirring solution of compound 691 (2 g, 19.77 mmol) in THF:H₂O(4:1, 60 mL) was added potassium carbonate (5.4 g, 31.67 mmol) portionwise for 10 min at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (100 mL) and extracted withEtOAc (2×75 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 20%EtOAc/hexanes to afford compound 692 (1.1 g, crude) as yellow syrup.TLC: 40% EtOAc/hexanes (R_(f): 0.2); LC-MS: 67.76%; 236.0 (M⁺+1);(column; X Select CSH C-18, (50×3.0 mm, 2.5 μm); RT 2.12 min. 2.5 mM Aq.NH4OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min).

Synthesis of benzyl (S)-3-(((methylsulfonyl) oxy) methyl)pyrrolidine-1-carboxylate (693)

To a stirring solution of compound 692 (1.2 g, crude) in CH₂Cl₂ (10 mL)under inert atmosphere were added triethylamine (2.11 mL, 15.31 mmol),methanesulfonyl chloride (0.67 mL, 7.65 mmol) at 0° C.; warmed to RT andstirred for 4 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with water (50 mL) andextracted with CH₂Cl₂ (2×50 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to affordcrude compound 693 (2 g) as brown liquid. TLC: 40% EtOAc/hexanes (R_(f):0.4); LC-MS: 80.20%; 313.9 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm,2.6 um); RT 1.27 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5% 2.5 mMAq.NH₄OOCH, 0.8 mL/min).

Synthesis of benzyl (S)-3-((4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenoxy) methyl) pyrrolidine-1-carboxylate (694)

To a stirring solution of compound 693 (230 mg, 0.98 mmol) in DMF (3 mL)under inert atmosphere were added tert-butyl ((2-(4-hydroxyphenyl)thiazol-5-yl) methyl) carbamate 356 (200 mg, 0.65 mmol), cesiumcarbonate (424 mg, 1.36 mmol) at RT and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with water (50 mL) and extracted with EtOAc (2×75mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to afford crude compound 694 (300 mg)as yellow solid. TLC: 40% EtOAc/hexanes (R_(f): 0.4); LC-MS: 63.70%;524.5 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 1.27min. 2.5 mM Aq. NH₄OAc: ACN, 0.8 mL/min).

Synthesis of benzyl (S)-3-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy)methyl) pyrrolidine-1-carboxylate hydrochloride (695)

To a stirring solution of compound 694 (1.4 g, crude) in CH₂Cl₂ (10 mL)was added 4 N HCl in 1, 4-dioxane (10 mL) under inert atmosphere at 0°C.; warmed to RT and stirred for 3 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The crude washed with diethyl ether (5 mL), EtOAc (5 mL) and dried invacuo to afford compound 695 (1 g, crude) as brown solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.1); LC-MS: 69.41%; 424.1 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.08 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl (S)-3-((4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) methyl) pyrrolidine-1-carboxylate (696)

To a stirring solution of 92 (400 mg, 1.32 mmol) in DMF (5 mL) underinert atmosphere were added HOBt (356 mg, 2.64 mmol), EDCI.HCl (506 mg,2.64 mmol), diisopropyl ethyl amine (0.68 mL, 3.96 mmol) and compound695 (722 mg, crude) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with ice-cold water (50 mL) and extractedwith EtOAc (2×75 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using 2%MeOH/CH₂Cl₂ to afford compound 696 (400 mg, 43%) as an off-white solid.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.52 (s,1H), 9.45 (t, J=5.8 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.98 (td, J=7.7,1.3 Hz, 2H), 7.93-7.84 (m, 3H), 7.84-7.77 (m, 3H), 7.72 (s, 1H),7.38-7.33 (m, 4H), 7.33-7.28 (m, 1H), 7.07-6.98 (m, 2H), 5.06 (s, 2H),4.66 (d, J=5.6 Hz, 2H), 4.13-3.93 (m, 2H), 3.61-3.41 (m, 2H), 3.40-3.34(m, 1H), 3.25-3.13 (m, 1H), 2.71-2.60 (m, 1H), 2.12-1.96 (m, 1H),1.83-1.68 (m, 1H); LC-MS: 84.44%; 709.2 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.98 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (S)-11-oxo-N-((2-(4-(pyrrolidin-3-ylmethoxy) phenyl)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11139)

To a stirring solution of compound 696 (200 mg, 0.28 mmol) in CH₂Cl₂ (10mL) was added trimethylsilyl iodide (0.03 mL, 0.211 mmol) under inertatmosphere at 0° C.; warmed to RT and stirred for 4 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The crude washed with EtOAc (10 mL) and dried in vacuoto afford crude amine.

To the above crude amine (150 mg) in CH₂Cl₂ (5 mL) under inertatmosphere was added 4 N HCl in 1, 4-dioxane (3 mL) at 0° C. and stirredfor 1 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo. The crude washed withtriturated with diethylether (10 mL) and dried in vacuo to afford crudecompound HCl (140 mg) which was further purified by preparative HPLCpurification to afford 11139 (89 mg, HCl salt, 36%) as an off-whitesolid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ11.51 (s, 1H), 9.45 (t, J=5.8 Hz, 1H), 8.67 (br s, 2H), 8.05 (d, J=8.2Hz, 1H), 7.97 (td, J=7.5, 1.3 Hz, 2H), 7.92-7.78 (m, 6H), 7.72 (s, 1H),7.03 (d, J=8.9 Hz, 2H), 4.65 (d, J=5.6 Hz, 2H), 4.13-3.90 (m, 2H),3.44-3.35 (m, 1H), 3.21-3.12 (m, 2H), 3.06-2.98 (m, 1H), 2.78-2.70 (m,1H), 2.19-1.98 (m, 1H), 1.83-1.66 (m, 1H); LC-MS: 98.88%; 575.1 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.98 min. 0.025%Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):99.73%; (column; X-Select CSH-C-18 (150×4.6 mm, 3.5 μm); RT 5.61 min.0.05% TFA (Aq)+5% ACN: ACN+5% 0.05% TFA (Aq); 1.0 mL/min, Diluent:ACN:H₂O:DMSO).

Synthesis of 11140

Synthesis of (R)-pyrrolidin-3-ylmethanol.TFA Salt (698)

To a stirring solution of tert-butyl (R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate 697 (2 g, 9.95 mmol) in CH₂Cl₂ (20 mL) wasadded trifluoroacetic acid (20 mL) at 0° C. under inert atmosphere. Thereaction mixture was gradually warmed to RT and stirred for 3 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The crude was triturated withdiethylether (20 mL), n-hexane (30 mL) and dried under vacuum to affordcrude compound 698 (1.8 g) as pale yellow sticky syrup. This crudematerial was taken to next step without further purification. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.1); LC-MS (Agilent 6310 Ion trap): 32.89%; 102.3(M⁺+1); (column; X-select CSH C-18 (150×4.6 mm, 3.5 um); RT 1.95 min.2.5 mM Aq. NH₄OAc: ACN; 1.0 mL/min).

Synthesis of benzyl (R)-3-(hydroxymethyl) pyrrolidine-1-carboxylate(699)

To a stirring solution of compound 698 (1.8 g, crude) in a mixture ofTHF:H₂O (1:1, 60 mL) were added potassium carbonate (4.92 g, 35.64 mmol)and benzyl chloroformate (50% in toluene, 10.22 mL, 35.64 mmol) at 0° C.The reaction mixture was gradually warmed to RT and stirred for 16 h.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with EtOAc (100 mL) and washed with water(50 mL). The organic layer was separated, dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 50%EtOAc/hexanes to afford compound 699 (1.3 g) as pale yellow liquid. Thismaterial with minor impurity was taken to next step. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H NMR (500 MHz, DMSO-d₆): δ 7.44-7.25 (m,5H), 5.05 (s, 2H), 4.66 (q, J=4.6 Hz, 1H), 3.52-3.34 (m, 4H), 3.30-3.20(m, 1H), 3.10-3.06 (m, 1H), 2.37-2.20 (m, 1H), 1.92-1.82 (m, 1H),1.66-1.54 (m, 1H); LC-MS: 76.88%; 236.0 (M⁺+1); (column; Kinetex EVOC-18 (50×3.0 mm, 2.6 um); RT 2.13 min. 2.5 mM NH₄OOCH in water+5% ACN:ACN+5% 2.5 mM NH₄OOCH in water, 0.8 mL/min).

Synthesis of benzyl (R)-3-(((methylsulfonyl) oxy) methyl)pyrrolidine-1-carboxylate (700)

To a stirring solution of compound 699 (1.3 g, 5.53 mmol) in CH₂Cl₂ (30mL) were added triethylamine (2.32 mL, 16.59 mmol) and methanesulfonylchloride (0.51 mL, 6.64 mmol) at 0° C. under inert atmosphere. Thereaction mixture was gradually warmed to RT and stirred for 4 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with CH₂Cl₂ (50 mL) and washed with water(50 mL). The organic layer was separated, dried over sodium sulfate,filtered and concentrated in vacuo to afford compound 700 (1.5 g) aspale yellow viscous syrup. This crude material was taken to next stepwithout further purification. TLC: 50% EtOAc/hexanes (R_(f): 0.3);LC-MS: 81.89%; 313.9 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm, 2.6um); RT 2.64 min. 2.5 mM NH₄OOCH in water+5% ACN: ACN+5% 2.5 mM NH₄OOCHin water, 0.8 mL/min).

Synthesis of benzyl (R)-3-((4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenoxy) methyl) pyrrolidine-1-carboxylate (701)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (800 mg, 2.61 mmol) in DMF (15 mL) were addedcompound 700 (1.53 g, crude) and cesium carbonate (1.7 g, 5.23 mmol) atRT in a sealed tube under inert atmosphere. The reaction mixture washeated to 70° C. and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith water (50 mL) and extracted with EtOAc (2×150 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to afford compound 701 (800 mg) as pale yellowviscous syrup. This crude material was taken to next step withoutfurther purification. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.6); LC-MS: 53.55%;524.2 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 3.73min. 2.5 mM NH₄OOCH in water+5% ACN: ACN+5% 2.5 mM NH₄OOCH in water, 0.8mL/min).

Synthesis of benzyl (R)-3-((4-(5-(aminomethyl) thiazol-2-yl) phenoxy)methyl) pyrrolidine-1-carboxylate hydrochloride (702)

To a stirring solution of compound 701 (500 mg, crude) in CH₂Cl₂ (10 mL)was added 4 N HCl in 1, 4-dioxane (5 mL) at 0° C. under inertatmosphere. The reaction mixture was gradually warmed to RT and stirredfor 3 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo. The crude was trituratedwith diethyl ether (10 mL), n-pentane (10 mL) and dried in vacuo toafford compound 702 (450 mg) as colorless sticky solid. This crudematerial was taken to next step without further purification. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.1); LC-MS (Agilent 6310 Ion trap): 66.70%; 424.3(M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 3.53 min. 5 mMAq. NH₄OAc: ACN, 0.8 mL/min).

Synthesis of benzyl (R)-3-((4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido)methyl)thiazol-2-yl) phenoxy) methyl) pyrrolidine-1-carboxylate (703)

To a stirring solution of 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide 92 (250 mg, 0.82 mmol) in DMF(10 mL) were added compound 702 (419 mg, crude) and HOBt (167 mg, 1.24mmol), EDCI.HCl (238 mg, 1.24 mmol) followed by diisopropylethylamine(0.72 mL, 4.12 mmol) at 0° C. under inert atmosphere. The reactionmixture was gradually warmed to RT and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with water (50 mL) and extracted with EtOAc (2×150mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude wastriturated with EtOAc (20 mL), CH₂Cl₂ (20 mL), n-pentane (20 mL) anddried under vacuum to afford compound 703 (230 mg) as colorless stickysolid. This crude material was taken to next step without furtherpurification. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H NMR (500 MHz,DMSO-d₆): δ 11.51 (br s, 1H), 9.45 (t, J=5.5 Hz, 1H), 8.06 (d, J=8.1 Hz,1H), 7.98 (t, J=8.7 Hz, 2H), 7.90 (t, J=7.2 Hz, 1H), 7.87-7.78 (m, 6H),7.72 (s, 1H), 7.38-7.29 (m, 4H), 7.03 (J=8.1 Hz, 2H), 5.06 (s, 2H),4.72-4.64 (m, 2H), 4.11-3.97 (m, 2H), 3.61-3.46 (m, 2H), 3.24-3.16 (m,1H), 3.00-2.94 (m, 2H), 1.82-1.71 (m, 1H), 1.50-1.45 (m, 1H); LC-MS:68.55%; 709.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 2.71 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of (R)-11-oxo-N-((2-(4-(pyrrolidin-3-ylmethoxy) phenyl)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11140)

To a stirring solution of compound 703 (230 mg, crude) in CH₂Cl₂ (5 mL)was added trimethylsilyl iodide (0.06 mL, 0.45 mmol) at 0° C. underinert atmosphere and stirred at the same temperature for 3 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The residue was diluted with CH₂Cl₂ (30mL) and washed with saturated sodium bicarbonate solution (20 mL). Theorganic layer was separated, dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography in basic Al₂O₃ using 10%MeOH/CH₂Cl₂ to afford 11140 (18 mg, 8%) as an off white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H NMR (400 MHz, DMSO-d₆): δ 9.45 (t, J=5.5Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.78 (m, 6H),7.72 (s, 1H), 7.02 (d, J=8.8 Hz, 2H), 4.66 (d, J=5.4 Hz, 2H), 4.00-3.89(m, 2H), 3.46-3.37 (m, 1H), 3.03-2.89 (m, 2H), 2.83-2.80 (m, 1H),2.73-2.66 (m, 1H), 1.95-1.84 (m, 1H), 1.53-1.45 (m, 1H); LC-MS: 96.04%;575.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT1.82 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);HPLC (purity): 95.84%; (column; X-Select CSH-C-18 (150×4.6 mm, 3.5 μm);RT 5.64 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent:ACN:H₂O).

Synthesis of 11103

Synthesis of benzyl (S)-3-hydroxypyrrolidine-1-carboxylate (705)

To a stirring solution of (S)-pyrrolidin-3-ol 704 (1.5 g, 17.22 mmol) inCH₂Cl₂ (50 mL) under inert atmosphere were added triethylamine (7.4 mL,51.72 mmol), benzyl chloroformate (50% in toluene, 7.05 mL, 20.66 mmol)at 0° C.; warmed to RT and stirred for 16 h. The reaction was monitoredby TLC; after completion, the reaction mixture was poured into ice-coldwater and extracted with CH₂Cl₂ (2×60 mL). The combined organic extractswere washed dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through columnchromatography using 50% EtOAc/hexanes to afford compound 705 (2 g, 53%)as pale yellow liquid. TLC: 60% EtOAc/hexanes (R_(f): 0.5); ¹H NMR(DMSO-d₆, 500 MHz): δ 7.38-7.32 (m, 4H), 7.32-7.27 (m, 1H), 5.05 (s,2H), 4.91 (br s, 1H), 4.26-4.24 (m, 1H), 3.42-3.27 (m, 3H), 3.24-3.13(m, 1H), 1.91-1.81 (m, 1H), 1.78-1.70 (m, 1H); LC-MS: 98.78%; 222.0(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.85 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl (R)-3-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenoxy) pyrrolidine-1-carboxylate (706)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (700 mg, 2.28 mmol) in diethyl ether (30 mL) underargon atmosphere were added benzyl(S)-3-hydroxypyrrolidine-1-carboxylate 705 (758 mg, 3.42 mmol),triphenylphosphine (1.19 g, 4.54 mmol), DIAD (0.906 mL, 4.57 mmol) at 0°C.; warmed to RT and stirred for 24 h. The reaction was monitored byTLC; after completion, the reaction mixture was poured into ice-coldwater and extracted with EtOAc (2×75 mL). The combined organic extractswere washed dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through columnchromatography using 50% EtOAc/hexanes to afford compound 706 (1.6 g,crude) as an off-white solid. TLC: 50% EtOAc/hexanes (R_(f): 0.5);LC-MS: 33.04%; 510.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 2.85 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min). LC-MS shows 65.46%, TPPO as major impurity at RT 2.25.

Synthesis of benzyl (R)-3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)pyrrolidine-1-carboxylate hydrochloride (707)

To a stirring solution of benzyl (R)-3-(4-(5-(((tert-butoxycarbonyl)amino) methyl) thiazol-2-yl) phenoxy) pyrrolidine-1-carboxylate 706 (1.6g, crude) in CH₂Cl₂ (30 mL) was added 4 N HCl in 1, 4-dioxane (3 mL)under argon atmosphere at 0° C.; warmed to RT and stirred for 2 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The crude washed with diethyl ether (10mL) and dried in vacuo to afford compound 707 (550 mg; HCl salt) as anoff-white solid. TLC: 50% EtOAc/hexanes (R_(f): 0.1); 41 NMR (DMSO-d₆,500 MHz): δ 8.54 (br s, 1H), 7.91 (s, 1H), 7.86 (d, J=8.7 Hz, 1H),7.40-7.32 (m, 1H), 7.09 (d, J=8.7 Hz, 1H), 5.23-4.97 (m, 1H), 4.32 (q,J=5.6 Hz, 1H), 3.80-3.31 (m, 1H), 2.29-2.05 (m, 1H); LC-MS: 99.37%;432.0 (M⁺+Na); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT1.93 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl (R)-3-(4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) pyrrolidine-1-carboxylate (708)

To a stirring solution of 92 (200 mg, 0.66 mmol) in DMF (15 mL) underinert atmosphere were added EDCI.HCl (190 mg, 0.99 mmol), HOBt (135 mg,0.99 mmol), benzyl (R)-3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)pyrrolidine-1-carboxylate hydrochloride 707 (299 mg, 0.66 mmol) anddiisopropylethylamine (0.63 mL, 3.30 mmol) at 0° C.; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was poured into ice-cold water (50mL) and extracted with EtOAc (2×60 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through silica gel (100-200mesh) column chromatography using 5% MeOH/CH₂Cl₂ to afford compound 708(300 mg, 67%) as an off-white solid. TLC: 4% MeOH/CH₂Cl₂ (R_(f): 0.4);¹H-NMR (DMSO-d₆, 500 MHz): δ 11.51 (s, 1H), 9.45 (t, J=5.8 Hz, 1H), 8.06(d, J=8.1 Hz, 1H), 8.01-7.96 (m, 2H), 7.90 (td, J=7.5, 1.2 Hz, 1H),7.87-7.79 (m, 5H), 7.73 (s, 1H), 7.42-7.26 (m, 5H), 7.04 (d, J=8.7 Hz,2H), 5.15-5.01 (m, 3H), 4.66 (br d, J=5.8 Hz, 2H), 3.71-3.60 (m, 1H),3.58-3.39 (m, 3H), 2.27-2.04 (m, 2H); LC-MS: 91.64%; 695.1 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.61 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (R)-11-oxo-N-((2-(4-(pyrrolidin-3-yloxy) phenyl)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11103)

To a stirring solution of benzyl (R)-3-(4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) pyrrolidine-1-carboxylate 708 (100 mg, 0.14 mmol)in t-butanol (10 mL) under inert atmosphere was added 10% Pd/C (50% wet,200 mg), ammonium formate (180 mg, 2.88 mmol) at RT; heated to 80° C.and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were concentrated in vacuo toobtain the crude. The crude was purified through silica gel (100-200mesh) column chromatography using 12% MeOH/CH₂Cl₂ to afford crude amine(30 mg).

To the above crude amine (30 mg) in CH₂Cl₂ (5 mL) under inert atmospherewas added 4 N HCl in 1, 4-dioxane (3 mL) at 0° C. and stirred for 30min. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo. The crude washed withtriturated with EtOAc (5 mL) and dried in vacuo to afford 11103 (22 mg,68.9%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR(DMSO-d₆, 400 MHz): δ 11.53 (s, 1H), 9.50 (t, J=5.8 Hz, 1H), 9.41-9.24(m, 2H), 8.06 (d, J=8.3 Hz, 1H), 7.98 (td, J=7.3, 1.5 Hz, 2H), 7.93-7.81(m, 6H), 7.74 (s, 1H), 7.06 (d, J=8.9 Hz, 2H), 5.21 (t, J=4.4 Hz, 1H),4.66 (d, J=5.6 Hz, 2H), 3.40-3.22 (m, 4H), 2.29-2.09 (m, 2H); LC-MS:92.21%; 561.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.81 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2mL/min); HPLC (purity): 97.17%; (column; X-select CSH C-18 (150×4.66 mm,3.5 μm); RT 5.28 min. ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0mL/min, Diluent: ACN:water)

Synthesis of 11028 & 11134

Synthesis of benzyl (R)-3-hydroxypyrrolidine-1-carboxylate (710)

To a stirring solution of (R)-pyrrolidin-3-ol 709 (1.5 g, 17.24 mmol) inCH₂Cl₂ (50 mL) under inert atmosphere were added triethylamine (7.4 mL,51.72 mmol), benzyl chloroformate (50% in toluene, 7.05 mL, 20.66 mmol)at 0° C.; warmed to RT and stirred for 16 h. The reaction was monitoredby TLC; after completion, the reaction mixture was poured into ice-coldwater and extracted with CH₂Cl₂ (2×60 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through column chromatographyusing 50% EtOAc/hexanes to afford compound 710 (1.5 g, 39%) as paleyellow liquid. TLC: 60% EtOAc/hexanes (R_(f): 0.5); ¹H NMR (DMSO-d₆, 500MHz): δ 7.40-7.34 (m, 4H), 7.33-7.28 (m, 1H), 5.06 (s, 2H), 4.93 (br s,1H), 4.26-4.24 (m, 1H), 3.42-3.30 (m, 3H), 3.23-3.17 (m, 1H), 1.93-1.82(m, 1H), 1.80-1.71 (m, 1H); LC-MS: 99.47%; 222.0 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.86 min. 0.025% Aq.TFA+5%ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl (S)-3-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenoxy) pyrrolidine-1-carboxylate (711)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (700 mg, 2.28 mmol) in diethyl ether (30 mL) underargon atmosphere were added benzyl(R)-3-hydroxypyrrolidine-1-carboxylate 710 (758 mg, 3.43 mmol),triphenylphosphine (1.19 g, 4.57 mmol), DIAD (0.906 mL, 4.57 mmol) at 0°C.; warmed to RT and stirred for 48 h. The reaction was monitored byTLC; after completion, the reaction mixture was poured into ice-coldwater and extracted with EtOAc (2×75 mL). The combined organic extractswere washed dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through columnchromatography using 50% EtOAc/hexanes to afford compound 711 (1.6 g,crude) as an off-white solid. TLC: 50% EtOAc/hexanes (R_(f): 0.4);LC-MS: 42.16%; 510.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 2.86 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min). LC-MS shows 53.36% TPPO as major impurity at RT 2.25.

Synthesis of benzyl (S)-3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)pyrrolidine-1-carboxylate hydrochloride (712)

To a stirring solution of benzyl (S)-3-(4-(5-(((tert-butoxycarbonyl)amino) methyl) thiazol-2-yl) phenoxy) pyrrolidine-1-carboxylate 711 (1.6g, crude) in CH₂Cl₂ (30 mL) was added 4 N HCl in 1, 4-dioxane (3 mL)under argon atmosphere at 0° C.; warmed to RT and stirred for 2 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo. The crude washed with diethyl ether (10mL) and EtOAc (2×5 mL) and dried in vacuo to afford compound 712 (510mg; HCl salt) as an off-white solid. TLC: 50% EtOAc/hexanes (R_(f):0.1); 41 NMR (DMSO-d₆, 400 MHz): δ 8.50 (br s, 3H), 7.91 (s, 1H), 7.86(d, J=8.7 Hz, 2H), 7.43-7.25 (m, 5H), 7.09 (d, J=8.9 Hz, 2H), 5.17-4.93(m, 3H), 4.32 (q, J=5.5 Hz, 2H), 3.74-3.61 (m, 1H), 3.60-3.36 (m, 3H),2.29-2.05 (m, 2H); LC-MS: 93.90%; 432.0 (M⁺+Na); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.94 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of benzyl (S)-3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) pyrrolidine-1-carboxylate (713)

To a stirring solution of 92 (200 mg, 0.66 mmol) in DMF (15 mL) underinert atmosphere were added EDCI.HCl (190 mg, 0.99 mmol), HOBt (135 mg,0.99 mmol), benzyl (S)-3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)pyrrolidine-1-carboxylate hydrochloride 712 (294 mg, 0.66 mmol) anddiisopropylethylamine (0.63 mL, 3.30 mmol) at 0° C.; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion,the reaction mixture was poured into ice-cold water (50 mL) andextracted with EtOAc (2×30 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silica gel (100-200 mesh) columnchromatography using 4% MeOH/CH₂Cl₂ to afford compound 713 (220 mg, 49%)as an off-white solid. TLC: 4% MeOH/CH₂Cl₂ (R_(f): 0.4); LC-MS: 82.34%;695.2 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT2.56 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of (S)-11-oxo-N-((2-(4-(pyrrolidin-3-yloxy) phenyl)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide TFA salt (11028)

To a stirring solution of benzyl (S)-3-(4-(5-((5,5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) pyrrolidine-1-carboxylate 713 (100 mg, 0.14 mmol)in CH₂Cl₂ (5 mL) under inert atmosphere was added trimethylsilyl iodide(0.02 mL, 0.014 mmol) at 0° C.; warmed to RT and stirred for 30 min. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were concentrated in vacuo to obtain the crude. The crude waspurified through column chromatography using 10% MeOH/CH₂Cl₂ followed bypreparative HPLC purification to afford 11028 (38 mg, 47%) as anoff-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (DMSO-d₆, 400MHz): δ 11.52 (s, 1H), 9.46 (t, J=5.8 Hz, 1H), 9.06 (br s, 1H), 8.90 (brs, 1H), 8.06 (d, J=8.3 Hz, 1H), 8.00-7.96 (m, 2H), 7.93-7.80 (m, 6H),7.74 (s, 1H), 7.06 (d, J=8.9 Hz, 2H), 5.21 (t, J=4.7 Hz, 1H), 4.67 (d,J=5.6 Hz, 2H), 3.51-3.43 (m, 2H), 3.39-3.26 (m, 2H), 2.27-2.21 (m, 1H),2.18-2.10 (m, 1H); LC-MS: 98.35%; 561.1 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.83 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 99.08%; (column;X-select CSH-C18 (150×4.6 mm, 3.5 μm); RT 5.73 min. 0.05% TFA (Aq)+5%ACN: ACN+5% 0.05% TFA (Aq): 1.0 mL/min, Diluent: ACN:water: DMSO).

Synthesis of (S)—N-((2-(4-((1-methylpyrrolidin-3-yl) oxy)phenyl)thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5,5-dioxide (11134)

To a stirring solution of 11028 (100 mg, 0.17 mmol) in MeOH (10 mL)under inert atmosphere were added paraformaldehyde (55 mg, 0.89 mmol)and sodium cyanoborohydride (26 mg, 0.89 mmol) at 0° C.; warmed to RTand stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(50 mL) and extracted with 10% MeOH/CH₂Cl₂ (2×30 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel (100-200 mesh) column chromatography using 8%MeOH/CH₂Cl₂ to afford 11134 (35 mg, 34%) as an off-white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.4); 41 NMR (DMSO-d₆, 400 MHz): δ 11.53 (s, 1H),9.48 (t, J=5.8 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 8.01-7.95 (m, 2H),7.93-7.80 (m, 6H), 7.73 (s, 1H), 7.01 (d, J=8.9 Hz, 2H), 5.11-5.05 (m,1H), 4.66 (d, J=5.5 Hz, 2H), 3.17-3.10 (m, 2H), 2.96-2.86 (m, 1H), 2.60(s, 3H), 2.57-2.54 (m, 1H), 2.44-2.37 (m, 1H), 2.02-1.93 (m, 1H); LC-MS:98.35%; 593.1 (M⁺+1); (Column; X-select CSH C-18 (150×4.6 mm, 3.5 μm);RT 1.89 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.0 mL/min);HPLC (purity): 97.97%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm);RT 6.45 min. 0.05% TFA (Aq)+5% ACN: ACN+5% 0.5% TFA (Aq); 1.0 mL/min,Diluent: ACN:water).

Synthesis of 11026

Synthesis of benzyl 4-hydroxypiperidine-1-carboxylate (714)

To a stirring solution of piperidin-4-ol 485 (1 g, 9.90 mmol) in CH₂Cl₂(10 mL) under argon atmosphere were added triethylamine (2.08 mL, 14.85mmol), Cbz-Cl (50% in toluene) (3.4 mL, 11.88 mmol) at 0° C.; warmed toRT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(40 mL) and extracted with CH₂Cl₂ (2×50 mL). The combined organicextracts were washed with water (50 mL) and brine (50 mL); dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using50% EtOAc/hexanes to afford compound 714 (1.3 g, 56%) as colorlessliquid. TLC: 70% EtOAc/hexanes (R_(f): 0.3); ¹H NMR (500 MHz, DMSO-d₆):δ 7.41-7.28 (m, 5H), 5.06 (s, 2H), 4.71 (d, J=4.1 Hz, 1H), 3.76-3.61 (m,3H), 3.08-3.04 (m, 2H), 1.75-1.67 (m, 2H), 1.34-1.23 (m, 2H); LC-MS:98.38%; 236.0 (M⁺+1); (column; Ascentis Express C-18, (50×3.0 mm, 2.7μm); RT 1.96 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min);

Synthesis of benzyl 4-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenoxy) piperidine-1-carboxylate (715)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate (356) (1 g, 3.26 mmol) in diethyl ether (30 mL) underargon atmosphere were added triphenylphosphine (2.56 g, 9.80 mmol), DIAD(1.98 g, 9.80 mmol) and benzyl 4-hydroxypiperidine-1-carboxylate 714(921 mg, 3.92 mmol) at 0° C.; warmed to RT and stirred for 48 h. Thereaction was monitored by LCMS; after completion of the reaction, thevolatiles were removed in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 20-30%EtOAc/hexanes to afford compound 715 (2.2 g, impure) as pale yellowliquid. This material was taken to next step without furtherpurification. TLC: 50% EtOAc/hexanes (R_(f): 0.5); LC-MS: 19.62%; 524.1(M⁺+1); (column; Ascentis Express C-18 (50×3.0 mm, 2.7 μm); RT 3.00 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of benzyl 4-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)piperidine-1-carboxylate (716)

To a stirring solution of compound 715 (2.2 g, crude. 4.20 mmol) inCH₂Cl₂ (10 mL) was added 4 N HCl in 1, 4-dioxane (5 mL) under argonatmosphere at 0° C.; warmed to RT and stirred for 2 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The crude washed with diethyl ether (5 mL) and EtOAc(5 mL) and dried in vacuo to afford compound 716 (420 mg, HCl salt) aswhite solid. TLC: 50% EtOAc/hexanes (R_(f): 0.1); ¹H NMR (500 MHz,DMSO-d₆): δ 8.44 (br s, 3H), 7.88 (s, 1H), 7.83 (d, J=8.7 Hz, 2H),7.39-7.29 (m, 5H), 7.09 (d, J=8.7 Hz, 2H), 5.08 (s, 2H), 4.72-4.64 (m,1H), 4.33-4.27 (m, 2H), 3.77-3.69 (m, 2H), 3.34-3.24 (m, 2H), 1.99-1.92(m, 2H), 1.63-1.53 (m, 2H); LC-MS: 75.11%; 424 (M⁺+1); (column; AscentisExpress C-18 (50×3.0 mm, 2.7 μm); RT 2.04 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of benzyl 4-(4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo[b, f] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl)phenoxy)piperidine-1-carboxylate (717)

To a stirring solution of 92 (200 mg, 0.66 mmol) in DMF (6 mL) underinert atmosphere were added EDCI.HCl (189 mg, 0.99 mmol), HOBt (135 mg,0.99 mmol), diisopropyl ethyl amine (0.60 mL, 3.30 mmol) and compound716 (333 mg, 0.72 mmol) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (20 mL) and extracted with EtOAc(2×30 mL). The combined organic extracts were washed with water (30 mL)and brine (30 mL); dried over sodium sulfate, filtered and concentratedin vacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 2% MeOH/CH₂Cl₂ to afford compound 717 (160mg, 34%) as white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.6); ¹H NMR (500MHz, DMSO-d₆): δ 11.51 (br s, 1H), 9.44 (t, J=5.5 Hz, 1H), 8.06 (d,J=8.1 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.78 (m, 6H), 7.72 (s, 1H),7.40-7.30 (m, 5H), 7.06 (d, J=8.7 Hz, 2H), 5.09 (s, 2H), 4.69-4.64 (m,3H), 3.75-3.69 (m, 2H), 1.98-1.89 (m, 2H), 1.63-1.52 (m, 2H), 1.31-1.15(m, 2H); LC-MS: 96.50%; 709.2 (M⁺+1) (column; Ascentis Express C-18(50×3.0 mm, 2.7 μm); RT 2.61 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq TFA, 1.2 mL/min).

Synthesis of 11-oxo-N-((2-(4-(piperidin-4-yloxy) phenyl) thiazol-5-yl)methyl)-10, 11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide5,5-dioxide (11026)

To a stirring solution of compound 717 (140 mg, 0.19 mmol) in CH₂Cl₂ (5mL) was added trimethylsilyl iodide (0.02 mL, 0.19 mmol) under inertatmosphere at 0° C.; and stirred for 30 min. The reaction was monitoredby TLC; after completion of the reaction, the volatiles were removed invacuo. The residue was diluted with water and basified to pH˜8 usingsaturated NaHCO₃ solution. The obtained solid was filtered and dried invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 10% MeOH/CH₂Cl₂ and 0.05 mL aqueous ammoniato afford compound 11026 (25 mg, 22%) as white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H NMR (400 MHz, DMSO-d₆): δ 9.45 (t, J=5.8Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.98 (td, J=7.6, 1.1 Hz, 2H), 7.92-7.84(m, 3H), 7.84-7.76 (m, 3H), 7.72 (s, 1H), 7.03 (d, J=8.8 Hz, 2H), 4.66(d, J=5.6 Hz, 2H), 4.53-4.47 (m, 1H), 3.02-2.96 (m, 2H), 2.69-2.60 (m,2H), 2.00-1.90 (m, 2H), 1.56-1.45 (m, 2H); LC-MS: 97.84%; 589.1 (M++1);(column; Ascentis Express C-18, (50×3.0 mm, 2.7 μm); RT 1.85 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):94.94%; (column; X select CSH C-18 (150×4.6 mm, 3.5 μm); RT 5.74 min.0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent: ACN:water:DMSO.

Synthesis of 1996

Synthesis of (tert-butoxycarbonyl) proline (719)

To a stirring solution of proline 718 (10 g, 86.96 mmol) in CH₂Cl₂ (100mL) were added triethyl amine (15.75 mL, 113.04 mmol) and di-t-butyldicarbonate (29.93 mL, 130.43 mmol) in CH₂Cl₂ (50 mL) at 0° C. underinert atmosphere. The reaction mixture was gradually warmed to RT andstirred for 4 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was quenched with saturated citricacid solution (100 mL). The organic layer was separated, washed withwater (100 mL) and concentrated in vacuo to afford compound 719 (13 g)as colorless liquid. This crude material was taken to next step withoutfurther purification. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (500MHz, DMSO-d₆): δ 12.47 (br s, 1H), 4.08-4.00 (m, 1H), 3.36-3.21 (m, 2H),2.22-2.07 (m, 1H), 1.87-1.73 (m, 3H), 1.45 (s, 9H).

Synthesis of tert-butyl 2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (720)

To a stirring solution of compound 719 (5 g, crude) in THF (100 mL) wereadded 4-Methylmorpholine (3.06 mL, 27.91 mmol) followed by isobutylchloroformate (4.56 mL, 34.88 mmol) at −30° C. under inert atmosphere.The reaction mixture was allowed to stir at −30° C. for 1 h. Thenfreshly prepared CH₂N₂ solution (˜75 mL) was added at −30° C. Thereaction mixture was gradually warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, theexcess of CH₂N₂ was quenched with acetic acid (2 mL) and the volatileswere concentrated in vacuo. The residue was diluted with water (100 mL)and extracted with EtOAc (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was dissolved in methanol (75 mL) and Ag₂O (6.45 g,27.91 mmol) was added in portion wise at 0° C. The reaction mixture wasstirred at RT for 2 h. Then CH₂Cl₂ (30 mL) was added and filteredthrough a pad of celite. The filtrate was concentrated in vacuo andpurified through flash column chromatography using 5% EtOAc/hexanes toafford compound 720 (2 g, 37%) as colorless oily liquid. TLC: 10%EtOAc/hexanes (R_(f): 0.2); ¹H NMR (400 MHz, CDCl₃): δ 4.25-4.03 (m,1H), 3.67 (s, 3H), 3.43-3.30 (m, 2H), 2.98-2.75 (m, 1H), 2.31 (dd,J=15.1, 9.7 Hz, 1H), 2.13-1.98 (m, 1H), 1.89-1.71 (m, 3H), 1.46 (s, 9H).

Synthesis of tert-butyl 2-(2-hydroxyethyl) pyrrolidine-1-carboxylate(721)

To a stirring solution of compound 720 (200 mg, 0.82 mmol) in THF (50mL) was added lithium aluminium hydride (38 mg, 0.99 mmol) at 0° C.under inert atmosphere. The reaction mixture was gradually warmed to RTand stirred for 3 h. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was cooled to 0° C., quenched with10% aqueous sodium hydroxide (2 mL) and stirred for 20 min, filteredthrough a pad of celite. The celite pad was eluted with EtOAc (30 mL).The filtrate was dried over sodium sulfate, filtered and concentrated invacuo to afford compound 721 (180 mg, 97%) as colorless oily liquid.TLC: 20% EtOAc/hexanes (R_(f): 0.1); ¹H NMR (500 MHz, DMSO-d₆): δ 4.36(t, J=4.9 Hz, 1H), 3.75-3.71 (m, 1H), 3.43-3.39 (m, 2H), 3.26-3.15 (m,2H), 1.91-1.63 (m, 6H), 1.39 (s, 9H); LC-MS (Agilent 6310 Ion trap):89.07%; 216.2 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT2.95 min. 2.5 mM Aq. NH₄OAc: ACN, 0.8 mL/min).

Synthesis of tert-butyl 2-(2-((methylsulfonyl) oxy) ethyl)pyrrolidine-1-carboxylate (722)

To a stirring solution of compound 721 (150 mg, 0.7 mmol) in CH₂Cl₂ (10mL) were added triethylamine (0.29 mL, 2.09 mmol) followed bymethanesulfonyl chloride (0.11 mL, 1.39 mmol) drop wise over a period of10 min. at 0° C. under inert atmosphere and allowed to stir at the sametemperature for 3 h. The reaction was monitored by TLC; after completionof the reaction, the reaction mixture was diluted with ice cold water(20 mL) and extracted with CH₂Cl₂ (2×30 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to afford compound 722 (120 mg) colorless oily liquid. This crudematerial was taken to next step without further purification. TLC: 40%EtOAc/hexanes (R_(f): 0.3).

Synthesis of tert-butyl 2-(2-(4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) ethyl) pyrrolidine-1-carboxylate (723)

To a stirring solution of N-((2-(4-hydroxyphenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide 595 (500 mg, 1.02 mmol) in DMF (5mL) were added compound 722 (900 mg, crude) and cesium carbonate (1 g,3.05 mmol) at 0° C. under inert atmosphere. The reaction mixture washeated to 70° C. and stirred for 18 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith water (50 mL) and extracted with EtOAc (2×60 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough flash column chromatography using 2-4% MeOH/CH₂Cl₂ to affordcompound 723 (90 mg, 13%) as an off white solid. TLC: 5% MeOH/CH₂Cl₂(R_(f): 0.4); ¹H NMR (500 MHz, DMSO-d₆): δ 11.51 (s, 1H), 9.44 (t, J=5.5Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 8.01-7.96 (m, 2H), 7.90 (t, J=7.0 Hz,1H), 7.88-7.78 (m, 5H), 7.72 (s, 1H), 6.99 (d, J=8.7 Hz, 2H), 4.66 (d,J=5.8 Hz, 2H), 4.09-4.00 (m, 2H), 3.91-3.84 (m, 1H), 3.26-3.22 (m, 2H),2.17-2.05 (m, 2H), 1.95-1.80 (m, 2H), 1.80-1.71 (m, 2H), 1.35 (s, 9H);LC-MS: 93.56%; 589.2 (M⁺-Boc+1); (column; Kinetex EVO C-18 (50×3.0 mm,2.6 um); RT 3.47 min. 2.5 mM NH₄OOCH in water+5% ACN: ACN+5% 2.5 mMNH₄OOCH in water, 0.8 mL/min).

Synthesis of 11-oxo-N-((2-(4-(2-(pyrrolidin-2-yl) ethoxy) phenyl)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1996)

To a stirring solution of compound 723 (80 mg, 0.12 mmol) in CH₂Cl₂ (5mL) was added 4 N HCl in 1, 4-dioxane (0.2 mL) at 0° C. under inertatmosphere. The reaction mixture was gradually warmed to RT and stirredfor 2 h. The reaction was monitored by TLC; after completion of thereaction, the volatiles were removed in vacuo to obtain the crude. Thecrude was washed with CH₂Cl₂ (15 mL), n-hexane (15 mL) and dried invacuo to afford 1996 (50 mg, 73%, HCl salt) as an off white solid. TLC:5% MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H NMR (400 MHz, DMSO-d₆): δ 11.53 (s, 1H),9.48 (t, J=5.8 Hz, 1H), 9.04 (br s, 1H), 8.59 (br s, 1H), 8.06 (d, J=8.3Hz, 1H), 8.01-7.95 (m, 2H), 7.90 (td, J=7.5, 1.6 Hz, 1H), 7.87-7.80 (m,5H), 7.73 (s, 1H), 7.04 (d, J=8.9 Hz, 2H), 4.66 (d, J=5.6 Hz, 2H),4.19-4.08 (m, 2H), 3.64-3.56 (m, 1H), 3.26-3.08 (m, 2H), 2.22-2.06 (m,3H), 1.98-1.82 (m, 2H), 1.67-1.57 (m, 1H); LC-MS: 99.79%; 589.1 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.84 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):96.60%; (column; X-Select CSH-C-18 (150×4.6 mm, 3.5 μm); RT 5.68 min.0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent: ACN:H₂O:DMSO).

Synthesis of 11107 and 11107-A

Synthesis of methyl pyrrolidine-3-carboxylate hydrochloride (725)

To a stirring solution of pyrrolidine-3-carboxylic acid 724 (4 g, 34.78mmol) in methanol (60 mL) under inert atmosphere was added thionylchloride (3.8 mL, 52.17 mmol) drop wise at 0° C. The reaction mixturewas heated to reflux temperature and stirred for 4 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo to afford compound 725 (4 g, HCl salt) as colorlesssyrup. This crude material was taken to next step without furtherpurification. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H NMR (400 MHz,DMSO-d₆): δ=9.72-9.52 (m, 2H), 3.65 (s, 3H), 3.39-3.33 (m, 1H),3.31-3.23 (m, 2H), 3.20-3.16 (m, 1H), 3.14-3.11 (m, 1H), 2.24-2.11 (m,1H), 2.08-1.95 (m, 1H).

Synthesis of methyl 1-(3-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenoxy) propyl) pyrrolidine-3-carboxylate (726)

To a stirring solution of 3-(4-(5-(((tert-butoxycarbonyl) amino) methyl)thiazol-2-yl) phenoxy) propyl methanesulfonate 386 (3 g, crude) in DMF(25 mL) under inert atmosphere were added compound 725 (1.67 g, crude),potassium carbonate (2.8 g, 20.31 mmol) at RT; heated to 80° C. andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with water (100 mL) andextracted with EtOAC (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 5% MeOH/CH₂Cl₂ to afford compound 726 (1.1 g, 34%)as colorless viscous syrup. TLC: 5% MeOH/CH₂Cl₂ (R_(f). 0.5); ¹H NMR(500 MHz, DMSO-d₆): δ 7.81 (d, J=8.7 Hz, 2H), 7.60 (s, 1H), 7.53 (br s,1H), 7.02 (d, J=8.7 Hz, 2H), 4.31 (d, J=5.8 Hz, 2H), 4.06 (t, J=6.4 Hz,2H), 3.61 (s, 3H), 3.05-3.02 (m, 1H), 2.82-2.69 (m, 2H), 2.57-2.54 (m,3H), 2.07-1.84 (m, 5H), 1.40 (s, 9H); LC-MS: 78.25%; 476.2 (M⁺+1);(column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 2.69 min. 2.5 mMNH₄OOCH in water+5% ACN: ACN+5% 2.5 mM NH₄OOCH in water, 0.8 mL/min).

Synthesis of methyl 1-(3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)propyl) pyrrolidine-3-carboxylate hydrochloride (727)

To a stirring solution of compound 726 (1.1 g, 2.31 mmol) in CH₂Cl₂ (2.5mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (8 mL) dropwise at 0° C.; warmed to RT and stirred for 3 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo to obtain the crude. The crude was washed with EtOAc(2×5 mL), diethylether (2×5 mL) and dried in vacuo to afford compound727 (700 mg, HCl salt) as an off white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f). 0.1); LC-MS: 67.23%; 376.3 (M⁺+1); (column; Cortecs C18 (50×3.0mm, 2.7 μm); RT 3.04 min. 2.5 mM Aq. NH₄HCO₃: ACN, 0.8 mL/min).

Synthesis of methyl 1-(3-(4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) propyl) pyrrolidine-3-carboxylate (11107-A)

To a stirring solution of 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide 92 (200 mg, 0.66 mmol) in DMF(20 mL) were added compound 727 (325 mg, 0.79 mmol), EDCI.HCl (190 mg,0.99 mmol), HOBt (136 mg, 0.99 mmol) followed by diisopropylethylamine(0.34 mL, 1.98 mmol) at 0° C. under inert atmosphere. The reactionmixture was gradually warmed to RT and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with water (30 mL) and extracted with EtOAc (2×50mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through column chromatography using 5% MeOH/CH₂Cl₂ to afford11107-A (180 mg, 41%) as an off white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.7); ¹H NMR (400 MHz, DMSO-d₆): δ 11.52 (s, 1H), 9.45 (t, J=5.7Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.84 (m, 3H),7.83-7.77 (m, 3H), 7.72 (s, 1H), 7.01 (d, J=8.9 Hz, 2H), 4.66 (d, J=5.5Hz, 2H), 4.06 (t, J=6.3 Hz, 2H), 3.61 (s, 3H), 3.11-3.01 (m, 1H),2.92-2.71 (m, 2H), 2.63-2.55 (m, 2H), 2.45-2.39 (m, 2H), 2.17-1.84 (m,4H); LC-MS: 97.88%; 661.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0mm, 2.7 μm); RT 1.89 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min).

Synthesis of 1-(3-(4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy)propyl) pyrrolidine-3-carboxylic acid (11107)

To a stirring solution of methyl 1-(3-(4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenoxy) propyl) pyrrolidine-3-carboxylate 11107-A (90 mg,0.13 mmol) in a mixture of THF:MeOH:H₂O (2:1:1, 8 mL) was added lithiumhydroxide monohydrate (17 mg, 0.41 mmol) at 0° C. The reaction mixturewas gradually warmed to RT and stirred for 2 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The residue was acidified with 2 N HCl to pH˜5 andextracted with EtOAc (2×30 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was triturated with diethylether (2×5 mL) and dried invacuo to afford 11107 (30 mg, 34%) as an off white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H NMR (400 MHz, DMSO-d₆): δ 11.53 (br s, 1H),9.50 (t, J=5.8 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 8.01-7.95 (m, 2H),7.92-7.78 (m, 6H), 7.72 (s, 1H), 7.01 (d, J=8.9 Hz, 2H), 4.66 (d, J=5.6Hz, 2H), 4.07 (t, J=6.3 Hz, 2H), 3.02-2.96 (m, 2H), 2.85-2.78 (m, 1H),2.77-2.63 (m, 4H), 2.03-1.92 (m, 4H); LC-MS: 96.27%; 647.1 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.84 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):94.30%; (column; X-Select CSH-C-18 (150×4.6 mm, 3.5 μm); RT 5.63 min.0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent: ACN:H₂O:DMSO).

Synthesis of 1988

Synthesis of tert-butyl ((2-(4-(3-(2, 2, 2-trifluoroacetamido) propoxy)phenyl) thiazol-5-yl) methyl) carbamate (728)

To a stirring solution of tert-butyl ((2-(4-(3-aminopropoxy) phenyl)thiazol-5-yl) methyl) carbamate 404 (250 mg, 0.68 mmol) in CH₂Cl₂ (10mL) under inert atmosphere was added triethylamine (0.29 mL, 2.06 mmol),followed by addition of trifluoroacetic anhydride (0.11 mL, 0.82 mmol)for 5 min at 0° C.; warmed to RT and stirred for 3 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with 10% H₂O/MeOH (10 mL) and the volatiles were removed invacuo to obtain the crude. The crude was triturated with diethylether(2×10 mL) and dried in vacuo to afford compound 728 (230 mg, 73%) as anoff-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.8); ¹H NMR (DMSO-d₆, 500MHz): δ 9.50 (t, J=5.2 Hz, 1H), 7.82 (d, J=8.7 Hz, 2H), 7.61 (s, 1H),7.53 (t, J=5.5 Hz, 1H), 7.02 (d, J=8.7 Hz, 2H), 4.31 (d, J=5.8 Hz, 2H),4.06 (t, J=6.1 Hz, 2H), 3.37 (q, J=6.4 Hz, 2H), 1.96 (p, J=6.5 Hz, 2H),1.40 (s, 9H); LC-MS: 97.62%; 460.1 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 2.64 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-(3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propyl)-2,2, 2-trifluoroacetamide hydrochloride (729)

To a stirring solution of compound 728 (230 mg, 0.50 mmol) in CH₂Cl₂ (10mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (1 mL) at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with EtOAc (2×10 mL),and dried in vacuo to afford compound 729 (180 mg, HCl salt) as anoff-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500MHz): δ 9.53 (t, J=5.8 Hz, 1H), 8.54 (br s, 3H), 7.90 (s, 1H), 7.86 (d,J=8.7 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 4.31 (q, J=5.6 Hz, 2H), 4.07 (t,J=6.1 Hz, 2H), 3.42-3.33 (m, 2H), 1.97 (p, J=6.5 Hz, 2H);

Synthesis of 11-oxo-N-((2-(4-(3-(2, 2, 2-trifluoroacetamido) propoxy)phenyl) thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (730)

To a stirring solution of 92 (150 mg, 0.49 mmol) in DMF (10 mL) underinert atmosphere were added EDCI.HCl (142 mg, 0.74 mmol), HOBt (100 mg,0.74 mmol), diisopropylethylamine (0.72 mL, 2.47 mmol) and compound 729(195 mg, 0.54 mmol) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (100 mL) and extracted withEtOAc (2×75 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 5%MeOH/CH₂Cl₂ to afford compound 730 (180 mg, 57%) as an off-white solid.TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.8); ¹H-NMR (DMSO-d₆, 400 MHz): 11.51 (brs, 1H), 9.68-9.29 (m, 2H), 8.05 (d, J=8.3 Hz, 1H), 8.00-7.95 (m, 2H),7.93-7.78 (m, 6H), 7.72 (s, 1H), 7.01 (d, J=8.9 Hz, 2H), 4.66 (d, J=5.4Hz, 2H), 4.05 (t, J=6.0 Hz, 2H), 3.40-3.33 (m, 2H), 1.95 (p, J=6.4 Hz,2H); LC-MS: 94.34%; 654.1 (M⁺+1) (column; Ascentis Express C18, (50×3.0mm, 2.7 μm); RT 2.46 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min).

Synthesis of N-((2-(4-(3-aminopropoxy) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1988)

To a stirring solution of compound 730 (140 mg, 0.21 mmol) in MeOH (10mL) under inert atmosphere was added potassium carbonate (90 mg, 0.65mmol) at RT; heated to 80° C. and stirred for 4 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo to obtain the crude. The crude was purified throughsilica gel column chromatography using 10% MeOH/CH₂Cl₂ (aqueous ammonia)to afford crude amine (200 mg).

To the above crude amine (200 mg) in CH₂Cl₂ (10 mL) under inertatmosphere was added 4 N HCl in 1, 4-dioxane (4 mL) at 0° C. and stirredfor 30 min. The reaction was monitored by TLC; after completion of thereaction, the volatiles were concentrated in vacuo to afford 1988 (85mg, 63%) as white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.54 (s, 1H), 9.54 (t, J=5.8 Hz, 1H), 8.14-8.07(m, 2H), 8.05 (d, J=8.2 Hz, 2H), 7.98 (td, J=7.5, 1.1 Hz, 2H), 7.93-7.80(m, 6H), 7.72 (s, 1H), 7.03 (d, J=8.9 Hz, 2H), 4.66 (d, J=5.5 Hz, 2H),4.12 (t, J=6.1 Hz, 2H), 3.00-2.88 (m, 2H), 2.05 (p, J=6.7 Hz, 2H);LC-MS: 96.04%; 549.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 1.80 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 95.01%; (column; X select CSH C-18 (150×4.6 mm,3.5 μm); RT 5.85 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min,Diluent: DMSO:ACN:water).

Synthesis of 1989

Synthesis of tert-butyl ((2-(4-(3-(2, 2, 2-trifluoro-N-methylacetamido)propoxy) phenyl) thiazol-5-yl) methyl) carbamate (731)

To a stirring solution of compound 380 (250 mg, 0.66 mmol) in CH₂Cl₂ (10mL) under inert atmosphere were added triethylamine (0.14 mL, 0.99mmol), followed by dropwise addition of trifluoroacetic anhydride (0.14mL, 0.99 mmol) for 5 min at 0° C.; warmed to RT and stirred for 4 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (50 mL) and extracted with EtOAc(2×75 mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silicagel column chromatography using 2% MeOH/CH₂Cl₂ toafford compound 731 (150 mg, 47%) as thick syrup. TLC: 5% MeOH/CH₂Cl₂(R_(f): 0.8); LC-MS: 81.19%; 474.1 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 pin); RT 2.72 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-(3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propyl)-2,2, 2-trifluoro-N-methylacetamide hydrochloride (732)

To a stirring solution of compound 731 (150 mg, 0.31 mmol) in CH₂Cl₂ (10mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (2 mL) at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude, which was triturated with EtOAc (2×5 mL),diethyl ether (5 mL) and dried in vacuo to afford compound 732 (100 mg,77%; HCl salt) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f). 0.1);¹H-NMR (DMSO-d₆, 400 MHz): δ 8.55 (br s, 3H), 8.37 (s, 1H), 8.10 (s,1H), 7.51 (d, 1H), 4.40 (q, J=5.6 Hz, 2H); LC-MS: 88.64%; 374.0 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.72 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 11-oxo-N-((2-(4-(3-(2, 2, 2-trifluoro-N-methylacetamido)propoxy) phenyl) thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1,4] thiazepine-8-carboxamide 5, 5-dioxide (733)

To a stirring solution of 92 (70 mg, 0.23 mmol) in DMF (8 mL) underinert atmosphere were added EDCI.HCl (66 mg, 0.34 mmol), HOBt (47 mg,0.34 mmol), diisopropylethylamine (0.12 mL, 0.69 mmol) and compound 732(103 mg, 0.25 mmol) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (50 mL) and extracted with EtOAc(2×50 mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silicagel column chromatography using 5% MeOH/CH₂Cl₂ toafford compound 733 (50 mg, 32%) as an off-white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.5); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.49 (br s, 1H),9.42 (t, J=5.7 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.98-7.92 (m, 2H),7.90-7.76 (m, 6H), 7.70 (s, 1H), 6.98 (d, J=9.0 Hz, 2H), 4.64 (d, J=5.6Hz, 2H), 4.11-3.96 (m, 2H), 3.64-3.51 (m, 2H), 2.97 (s, 3H), 2.08-1.94(m, 2H); LC-MS: 95.56%; 659.1 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 2.48 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min).

Synthesis of N-((2-(4-(3-(methylamino) propoxy) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1989)

To a stirring solution of compound 733 (50 mg, 0.07 mmol) in MeOH (5 mL)under inert atmosphere was added potassium carbonate (52 mg, 0.37 mmol)in a sealed tube at RT; heated to 70° C. and stirred for 3 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were removed in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using aqueous ammonia:MeOH:CH₂Cl₂ (1:1:8) to afford 1989 (25 mg, 59%) as an off-white solid.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2 ¹H NMR (DMSO-d₆, 400 MHz): δ 9.45 (t,J=5.8 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 8.00-7.95 (m, 2H), 7.90 (td,J=7.5, 1.4 Hz, 1H), 7.87-7.85 (m, 2H), 7.83-7.77 (m, 3H), 7.72 (s, 1H),7.01 (d, J=8.9 Hz, 2H), 4.66 (d, J=5.6 Hz, 2H), 4.07 (t, J=6.4 Hz, 2H),2.66 (t, J=6.9 Hz, 2H), 2.32 (s, 3H), 1.92-1.83 (m, 2H); LC-MS: 98.03%;563.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT1.81 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);HPLC (purity): 97.45%; (column; X select CSH C-18 (150×4.6 mm, 3.5 μm);RT 6.00 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent:DMSO:ACN:water).

Synthesis of 1990

Synthesis of 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propan-1-olhydrochloride (734)

To a stirring solution of tert-butyl ((2-(4-(3-hydroxypropoxy) phenyl)thiazol-5-yl) methyl) carbamate 385 (1.2 g, 3.29 mmol) in CH₂Cl₂ (20 mL)under inert atmosphere was added 4 N HCl in 1, 4-dioxane (4 mL) at 0°C.; warmed to RT and stirred for 3 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo.The crude triturated with diethyl ether (10 mL) and dried in vacuo toafford compound 734 (1.2 g; HCl salt) as an off-white solid. TLC: 5%EtOAc/hexanes (R_(f): 0.1); LC-MS: 97.67%; 264.9 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.35 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-((2-(4-(3-hydroxypropoxy) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (735)

To a stirring solution of 92 (1 g, 3.30 mmol) in DMF (25 mL) under inertatmosphere were added HATU (1.87 g, 4.95 mmol), diisopropylethylamine(2.4 mL, 13.20 mmol) and 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy)propan-1-ol hydrochloride 734 (1.09 g, 3.62 mmol) at 0° C. warmed to RTand stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the diluted with water (10 mL) and extractedwith EtOAc (2×75 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using 3%MeOH/CH₂Cl₂ to afford compound 735 (1 g, 56%) as an off-white solid.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.51 (s,1H), 9.44 (t, J=5.8 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 8.01-7.95 (m, 2H),7.93-7.84 (m, 3H), 7.84-7.78 (m, 3H), 7.72 (s, 1H), 7.01 (d, J=8.9 Hz,2H), 4.66 (d, J=5.6 Hz, 2H), 4.55 (t, J=5.1 Hz, 1H), 4.08 (t, J=6.4 Hz,2H), 3.61-3.50 (m, 2H), 1.87 (p, J=6.3 Hz, 2H);

Synthesis of 3-(4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b, f][1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) propylmethanesulfonate (736)

To a stirring solution of compound 735 (1.0 g, 1.82 mmol) in CH₂Cl₂ (20mL) under inert atmosphere were added triethylamine (0.5 mL, 3.62 mmol),methanesulfonyl chloride (0.15 mL, 1.82 mmol) at 0° C.; warmed to RT andstirred for 24 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with CH₂Cl₂ (100 mL),washed with water (2×50 mL) The organic extract was dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was triturated with n-pentane (10 mL) and dried in vacuo to affordcompound 736 (1 g, crude, mixture of mono and dimesylated compounds) ascolorless sticky solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); LC-MS: 41.67%;628.0 (M⁺+1) (monomesylated compound), 39.31%; 706.0 (M⁺+1) (dimesylatedcompound); (column; Ascentis Express C-18, (50×3.0 mm, 2.7 μm); RT 2.28min (monomesylated compound), 2.44 min (dimesylated compound); 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-((2-(4-(3-(tert-butylamino) propoxy) phenyl)thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1990)

To a stirring solution of compound 736 (500 mg, crude) in MeOH (10 mL)under inert atmosphere were added potassium carbonate (330 mg, 2.39mmol), 2-methylpropan-2-amine (0.42 mL, 3.98 mmol) in a sealed tube atRT; heated to 80° C. and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith water (50 mL) and extracted with 10% MeOH/CH₂Cl₂ (2×75 mL). Thecombined organic extract was dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude the volatiles were removed invacuo to obtain the crude. The crude was purified through basic aluminacolumn chromatography using 10% MeOH/CH₂Cl₂ to afford 1990 (50 mg, 9%,over 2 steps) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.1,eluted twice); ¹H NMR (DMSO-d₆, 400 MHz): δ 9.47 (t, J=5.6 Hz, 1H),8.36-8.29 (m, 1H), 8.05 (d, J=8.2 Hz, 1H), 8.00-7.95 (m, 2H), 7.93-7.77(m, 6H), 7.72 (s, 1H), 7.02 (br d, J=8.7 Hz, 2H), 4.66 (br d, J=5.3 Hz,2H), 4.11 (t, J=6.0 Hz, 3H), 2.81 (t, J=7.0 Hz, 2H), 2.00-1.88 (m, 2H),1.14 (s, 9H); LC-MS: 90.26%; 605.1 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 1.93 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 91.83%; (column; X selectCSH C-18 (150×4.6 mm, 3.5 μm); RT 6.37 min. 0.05% TFA+5% ACN: ACN+5%0.05% TFA; 1.0 mL/min, Diluent: ACN:water).

Synthesis of 11108

Synthesis of tert-butyl ((2-(4-(3-bromopropoxy) phenyl) thiazol-5-yl)methyl) carbamate (737)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (1 g, 3.27 mmol) in acetone (50 mL) were added1,3-dibromopropane 432 (1.7 mL, 16.35 mmol) and potassium carbonate (2.3g, 16.35 mmol) at RT under inert atmosphere. The reaction mixture washeated to reflux temperature and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the volatiles wereremoved in vacuo. The residue was diluted with EtOAc (60 mL), washedwith water (40 mL) followed by brine (20 mL). The organic layer wasseparated, dried over sodium sulfate, filtered and concentrated in vacuoto obtain the crude. The crude was purified through columnchromatography using 1% MeOH/CH₂Cl₂ to afford compound 737 (1.1 g, 79%)as an off white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.8); ¹H NMR (400MHz, DMSO-d₆): δ 7.82 (d, J=8.8 Hz, 2H), 7.61 (s, 1H), 7.53 (t, J=5.8Hz, 1H), 7.05 (d, J=8.9 Hz, 2H), 4.31 (d, J=6.0 Hz, 2H), 4.14 (t, J=6.0Hz, 2H), 3.68 (t, J=6.6 Hz, 2H), 2.30-2.24 (m, 2H), 1.40 (s, 9H).

Synthesis of (2-(4-(3-bromopropoxy) phenyl) thiazol-5-yl) methanaminehydrobromide (738)

To a stirring solution of compound 737 (200 mg, 0.47 mmol) in CH₂Cl₂ (5mL) was added hydrobromic acid in acetic acid (0.6 mL, 2.34 mmol) at 0°C. under inert atmosphere. The reaction mixture was gradually warmed toRT and stirred for 4 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo toobtain the crude. The crude was triturated with diethylether (2×10 mL)and dried in vacuo to afford compound 738 (200 mg, HBr salt) as an offwhite solid. TLC: 40% EtOAc/hexanes (R_(f): 0.1); ¹H NMR (400 MHz,DMSO-d₆): δ 8.26 (br s, 3H), 7.90-7.83 (m, 3H), 7.09 (d, J=8.9 Hz, 2H),4.35 (q, J=5.6 Hz, 2H), 4.16 (t, J=6.0 Hz, 2H), 3.68 (t, J=6.5 Hz, 2H),2.31-2.24 (m, 2H).

Synthesis of N-((2-(4-(3-bromopropoxy) phenyl) thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (739)

To a stirring solution of 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide 92 (200 mg, 0.66 mmol) inacetonitrile (10 mL) were added compound 738 (216 mg, 0.66 mmol),Propylphosphonic anhydride (0.98 mL, 3.3 mmol) and N-Methylmorpholine(0.37 mL, 3.3 mmol) at 0° C. under inert atmosphere. The reactionmixture was gradually warmed to RT and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the volatileswere removed in vacuo. The residue was diluted with EtOAc (40 mL),washed with water (20 mL) followed by brine (20 mL). The organic layerwas separated, dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was triturated with diethylether(2×10 mL) and dried in vacuo to afford compound 739 (181 mg, 45%) as anoff white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (500 MHz,DMSO-d₆): δ 11.52 (s, 1H), 9.45 (t, J=5.5 Hz, 1H), 8.06 (d, J=8.1 Hz,1H), 8.01-7.96 (m, 2H), 7.92-7.79 (m, 6H), 7.73 (s, 1H), 7.04 (d, J=8.7Hz, 2H), 4.66 (d, J=5.8 Hz, 2H), 4.14 (t, J=5.8 Hz, 2H), 3.67 (t, J=6.4Hz, 2H), 2.29-2.24 (m, 2H).

Synthesis of 1-(3-(4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy)propyl) quinuclidin-1-ium bromide (11108)

To a stirring solution of compound 739 (50 mg, 0.08 mmol) in a mixtureof THF/acetonitrile (1:1, 10 mL) was added Quinuclidine (9.5 mg, 0.08mmol) at RT under inert atmosphere. The reaction mixture was heated toreflux temperature and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was triturated with diethylether(2×10 mL), CH₃CN/MeOH (10%, 5 mL) and dried in vacuo. The obtained solidwas dissolved in CH₃CN/MeOH/H₂O (1:1:1, 3 mL) and lyophilized for 16 hto afford 11108 (30 mg, 57%) as an off white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.1); ¹H NMR (400 MHz, DMSO-d₆): δ 11.55 (br s, 1H), 9.46 (t,J=5.0 Hz, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.99-7.94 (m, 2H), 7.89 (td,J=7.4, 1.2 Hz, 1H), 7.86-7.80 (m, 4H), 7.79-7.71 (m, 2H), 7.03 (d, J=8.8Hz, 2H), 4.66 (d, J=5.5 Hz, 2H), 4.10 (t, J=5.8 Hz, 2H), 3.46-3.38 (m,6H), 3.27-3.23 (m, 2H), 2.22-2.12 (m, 2H), 2.10-2.05 (m, 1H), 1.90-1.82(m, 6H); LC-MS: 92.59%; 643.2 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 1.90 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min); HPLC (purity): 90.14%; (column; X-Select CSH-C-18(150×4.6 mm, 3.5 μm); RT 6.31 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA;1.0 mL/min, Diluent: ACN:H₂O).

Synthesis of 11108-B

Synthesis ofN-((2-(4-(3-43H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)propoxy)phenyl)thiazol-5-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide 5,5-dioxide (11108-B)

To a stirring solution of 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxylic acid 5, 5-dioxide 92 (200 mg, 0.66 mmol) in DMF(2 mL) were added HATU (376 mg, 0.99 mmol), diisopropylethylamine (0.36mL, 1.98 mmol) and compound 738 (215 mg, 0.66 mmol) at 0° C. under inertatmosphere. The reaction mixture was gradually warmed to RT and stirredfor 16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with water (5 mL) andextracted with EtOAc (2×5 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through silicagel column chromatographyusing 4% MeOH/CH₂Cl₂ to afford 11108-B (50 mg, 12%) as an off whitesolid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ11.52 (br s, 1H), 9.45 (t, J=5.6 Hz, 1H), 8.80 (dd, J=1.4, 4.4 Hz, 1H),8.62 (dd, J=1.3, 8.4 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.98 (dt, J=7.6,1.1 Hz, 2H), 7.93-7.79 (m, 6H), 7.73 (s, 1H), 7.58 (dd, J=4.4, 8.4 Hz,1H), 7.05 (d, J=8.8 Hz, 2H), 4.80 (t, J=6.3 Hz, 2H), 4.66 (br d, J=5.5Hz, 2H), 4.32 (t, J=6.2 Hz, 2H), 2.26 (p, J=6.3 Hz, 2H); LC-MS: 94.98%;668.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT2.37 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);HPLC (purity): 94.02%; (column; X-select CSH-C18 (150×4.6 mm, 3.5 μm);RT 10.06 min. 5 mM Aq. NH₄HCO₃: ACN; 1.0 mL/min, Diluent:DMSO:ACN:water).

Synthesis of N-((2-(4-(3-chloro-2-hydroxypropoxy) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (743): A common Intermediate

Synthesis of tert-butyl ((2-(4-(oxiran-2-ylmethoxy) phenyl)thiazol-5-yl) methyl) carbamate (741)

To a stirring solution of tert-butyl ((2-(4-hydroxyphenyl) thiazol-5-yl)methyl) carbamate 356 (2.5 g, 8.16 mmol) in DMF (50 mL) under inertatmosphere were added epichlorohydrin 740 (1.89 g, 20.42 mmol) andpotassium carbonate (2.8 g, 20.42 mmol) at RT; heated to 70-80° C. andstirred for 3 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was poured into ice-cold water (100mL) and the precipitated solid was filtered and titurated with 15%EtOAc/hexanes and dried in vacuo to afford compound 741 (1.9 g, 64%) asan off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.8); ¹H-NMR (DMSO-d₆,400 MHz): δ 7.82 (d, J=8.7 Hz, 2H), 7.61 (s, 1H), 7.53 (d, J=5.0 Hz,1H), 7.06 (d, J=8.9 Hz, 2H), 4.40 (dd, J=11.4, 2.7 Hz, 1H), 4.31 (br d,J=5.6 Hz, 2H), 3.90 (dd, J=11.4, 6.6 Hz, 1H), 3.38-3.33 (m, 1H),2.87-2.84 (m, 1H), 2.73 (dd, J=5.0, 2.6 Hz, 1H), 1.40 (s, 9H); LC-MS:83.49%; 363.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 2.42 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of 1-(4-(5-(aminomethyl) thiazol-2-yl)phenoxy)-3-chloropropan-2-ol hydrochloride (742)

To a stirring solution of compound 741 (1.9 g, 5.24 mmol) in CH₂Cl₂ (20mL) was added 4 N HCl in 1, 4-dioxane (15 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 4 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude washed with 50% EtOAc/hexanes (5 mL) and dried in vacuoto afford compound 742 (1.5 g, 86%; HCl salt) as white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 8.67 (br s, 3H),7.92 (s, 1H), 7.86 (d, J=9.0 Hz, 2H), 7.09 (br d, J=9.0 Hz, 2H), 4.30(q, J=5.2 Hz, 2H), 4.06 (s, 2H), 3.79-3.66 (m, 3H), 3.56 (s, 2H); LC-MS:90.32%; 298.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.50 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of N-((2-(4-(3-chloro-2-hydroxypropoxy) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (743)

To a stirring solution of compound 742 (1.2 g, 3.96 mmol) and 92 (1.0 g,3.30 mmol) in DMF (40 mL) under inert atmosphere were added HOBt (801mg, 5.94 mmol), EDCI.HCl (945 mg, 5.95 mmol), diisopropyl ethyl amine(2.1 mL, 11.88 mmol) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was poured into ice-cold water (30 mL) and extractedwith 10% MeOH/CH₂Cl₂ (2×250 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silicagel columnchromatography using 4% MeOH/CH₂Cl₂ to afford compound 743 (1.1 g, 48%)as white solid. TLC: 7% MeOH/CH₂Cl₂ (R_(f): 0.8); ¹H NMR (DMSO-d₆, 500MHz): δ 11.51 (s, 1H), 9.45 (br t, J=5.8 Hz, 1H), 8.06 (d, J=8.7 Hz,1H), 7.98 (t, J=8.4 Hz, 2H), 7.90 (td, J=7.5, 1.2 Hz, 1H), 7.87-7.79 (m,5H), 7.73 (s, 1H), 7.04 (d, J=8.7 Hz, 2H), 5.58 (d, J=4.6 Hz, 1H), 4.66(br d, J=5.8 Hz, 2H), 4.07-4.01 (m, 3H), 3.79-3.64 (m, 2H); LC-MS:89.09%; 584.0 (M++1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 2.22 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Preparation

Compound 743 was synthesized as mentioned above and converted to finalproducts as HCl salt/TFA salt/free amine using commercially availableamines employing typical procedures L and the results are captured inthe Table 4:

Typical Procedure L:

To a stirring solution of compound 743 (250 mg, 0.42 mmol) in EtOH (10mL) in a sealed tube was added 33% ethanolic ammonia (10 mL) at 0° C.;heated to 50° C. and stirred for 3 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuoand the residue washed with 20% EtOAc/hexanes and dried in vacuo toobtain the crude which was purified by preparative HPLCpurification/triturated to afford the desired product.

Commercial Amines Used for the Preparation

TABLE 4 Synthesis from compound 743 using various amines Proce- dure,Ex- Interme- Rx. Mass am- diate, Yield Spec. Mass Spec. ple Structureamine (%) Found Calculated ¹H-NMR 11084

L, 743, 240 38 579.0 (M⁺ + 1) 614.11 for C₂₈H₂₇ClN₄O₆S₂ ¹H-NMR (DMSO-d₆,400 MHz): δ 11.52 (s, 1H), 9.46 (t, J = 5.7 Hz, 1H), 8.49- 8.42 (m, 1H),8.06 (d, J = 8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.80 (m, 6H), 7.73 (s,1H), 7.04 (d, J = 8.9 Hz, 2H), 5.99-5.82 (m, 1H), 4.66 (br d, J = 5.6Hz, 2H), 4.17-4.10 (m, 1H), 4.02 (br d, J = 5.0 Hz, 3H), 3.19-3.10 (m,1H), 3.06-2.96 (m, 1H), 2.61 (t, J = 5.4 Hz, 3H); 11085

L^(a), 743, 243 25 593.1 (M⁺ + 1) 592.15 for C₂₉H₂₈N₄O₆S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.48 (m, 1H), 9.46 (t, J = 5.4, 1H), 8.06 (br d,J = 8.2 Hz, 1H), 7.98 (t, J = 7.8 Hz, 2H), 7.93-7.77 (m, 6H), 7.72 (s,1H), 7.02 (br d, J = 8.4 Hz, 2H), 4.87 (br s, 1H), 4.66 (br d, J = 4.7Hz, 2H), 4.02 (br d, J = 6.1 Hz, 1H), 3.94- 3.86 (m, 2H), 2.42- 37 (m,1H), 2.31- 2.25 (m, 1H), 2.18 (s, 6H); 11086

L^(b), 743, 387 41 621.1 (M+ + 1) 620.18 for C₃₁H₃₂N₄O₆S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.50 (br s, 1H), 9.44 (t, J = 5.7 Hz, 1H), 8.05(d, J = 8.2 Hz, 1H), 7.98 (dd, J = 7.5, 1.2 Hz, 2H), 7.93-7.77 (m, 6H),7.72 (s, 1H), 7.02 (d, J = 8.9 Hz, 2H), 4.83-4.75 (m, 1H), 4.66 (br d, J= 5.5 Hz, 2H), 4.05 (dd, J = 9.8, 3.2 Hz, 1H), 3.94-3.89 (m, 1H),3.89-3.82 (m, 1H), 2.57-2.44 (m, 3H), 2.44-2.41 (m, 2H), 2.39-2.36 (m,1H), 0.94 (t, J = 7.1 Hz, 6H); 11087

L^(c), 743, 412 31 621.1 (M⁺ + 1) 620.18 for C₃₁H₃₂N₄O₆S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (br s, 1H), 9.44 (t, J = 5.8 Hz, 1H), 8.05(d, J = 8.1 Hz, 1H), 8.01-7.95 (m, 2H), 7.92-7.84 (m, 3H), 7.82-7.79 (m,3H), 7.72 (s, 1H), 7.02 (d, J = 9.3 Hz, 2H), 4.75 (br s, 1H), 4.66 (brd, J = 5.2 Hz, 2H), 4.04 (dd, J = 9.9, 2.9 Hz, 1H), 3.96-3.82 (m, 2H),2.75 (td, J = 13.2, 6.4 Hz, 1H), 2.34 (br d, J = 5.8 Hz, 1H), 2.31 (brd, J = 5.8 Hz, 1H), 2.18 (s, 3H), 0.92 (dd, J = 6.4, 2.9 Hz, 6H); 11088

L^(b), 743, 469 25 621.1 (M⁺ + 1) 734.17 for C₃₃H₃₃F₃N₆O₈S₂ ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.53 (s, 1H), 9.47 (t, J = 5.8 Hz, 1H), 8.41-8.23 (m, 2H), 8.06 (d, J = 8.2 Hz, 1H), 8.01-7.96 (m, 2H), 7.93-7.80 (m,6H), 7.73 (s, 1H), 7.06 (d, J = 9.0 Hz, 2H), 5.91 (d, J = 4.7 Hz, 1H),4.66 (br d, J = 5.6 Hz, 2H), 4.16-4.09 (m, 1H), 4.08-4.05 (m, 2H),3.22-3.06 (m, 1H), 3.01-2.89 (m, 1H), 1.29 (s, 9H); L^(a): Dimethylamine (2 M sol. In THF, 4 mL), 80° C., 24 h. L^(b): compd: 743 (100 mg),Diethyl amine (37 mg, 3 equiv), EtOH (5 mL), 80° C., 24 h. L^(c): compd:743 (200 mg), N-methylpropan-2-amine (75 mg, 3 equiv), EtOH (10 mL), 80°C., 48 h in sealed tube

Synthesis of 11011

Synthesis of 3-((6-bromopyridin-3-yl) oxy) propan-1-ol (746)

To a stirring solution of 6-bromopyridin-3-ol (744) 1 g, 5.74 mmol) inDMF (10 mL) under inert atmosphere was added Cs₂CO₃ (5.5 g, 17.22 mmol)at RT and stirred for 5 min. Then 3-bromo-1-propanol 745 (0.86 g, 6.32mmol) was added and continued stirring at RT for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with water (20 mL) and extracted with EtOAc (2×20 mL). Theorganic extract was dried over sodium sulfate, filtered and concentratedin vacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 40% EtOAc/hexanes to afford compound 746(700 mg, 53%) as colorless syrup. TLC: 50% EtOAc/hexanes (R_(f): 0.2);¹H NMR (DMSO-d₆, 400 MHz): δ 8.11 (d, J=3.2 Hz, 1H), 7.53 (d, J=8.4 Hz,1H), 7.38 (dd, J=8.8, 3.1 Hz, 1H), 4.56 (t, J=5.2 Hz, 1H), 4.11 (t,J=6.4 Hz, 3H), 3.57-3.52 (m, 2H), 1.86 (p, J=6.3 Hz, 2H); LC-MS: 56.62%;231.8 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT1.73 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 2-bromo-5-(3-((tetrahydro-2H-pyran-2-yl) oxy) propoxy)pyridine (747)

To a stirring solution of compound 746 (700 mg, 3.03 mmol) in DCM (10mL) under inert atmosphere were added dihydropyran (305 mg, 3.63 mmol)and p-toluene sulfonic acid (5 mg) at 0-5° C.; stirred at RT for 16 h.The reaction was monitored by TLC and LC-MS; after completion volatileswere evaporated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 30% EtOAc/hexanes toafford compound 747 (700 mg, 73%) as colorless syrup. TLC: 30%EtOAc/hexanes (R_(f): 0.5); ¹H NMR (DMSO-d₆, 400 MHz): δ 8.12 (d, J=2.9Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.40 (dd, J=8.7, 3.2 Hz, 1H), 4.59-4.53(m, 1H), 4.12 (t, J=6.3 Hz, 2H), 3.81-3.65 (m, 2H), 3.48 (td, J=9.9, 6.3Hz, 1H), 3.44-3.38 (m, 1H), 1.97 (p, J=6.3 Hz, 2H), 1.78-1.65 (m, 1H),1.65-1.56 (m, 1H), 1.53-1.34 (m, 4H);

Synthesis of 5-(3-((tetrahydro-2H-pyran-2-yl) oxy) propoxy)-2-tributylstannyl) pyridine (748)

To a stirring solution of compound 747 (1 g, 3.17 mmol) in dry THF (20mL) under inert atmosphere was added n-BuLi (1.9 mL, 3.17 mmol) at −78°C. and stirred for 30 min. Then tributyltin chloride (3 g, 9.52 mmol)was added at −78° C. and continued stirring for 1 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas quenched with ammonium chloride solution (30 mL) and extracted withEtOAc (2×30 mL). The organic extract was dried over sodium sulfate,filtered and concentrated in vacuo to afford compound 748 (1.8 g, crude)as colorless syrup. TLC: 30% EtOAc/hexanes (R_(f): 0.7); LC-MS: 39.52%;528.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT2.60 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of 11-oxo-N-((2-(5-(3-((tetrahydro-2H-pyran-2-yl) oxy)propoxy) pyridin-2-yl) thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b,f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (749)

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide(535) (500 mg, 1.16 mmol) in 1, 4-dioxane (25 mL) under inert atmospherewere added compound 748 (1.8 g, 3.48 mmol) and Pd(dppf)Cl₂ (85 mg, 0.116mmol) at RT and purged under argon atmosphere 30 min; heated to 110° C.and stirred for 16 h. The reaction was monitored by TLC; aftercompletion the volatiles were removed in vacuo to obtain the crude. Thecrude was purified through combiflash column chromatography using 30%EtOAc/hexanes to afford compound 749 (75 mg, 10%) as an off-white solid.TLC: 30% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): LC-MS:94.65%; 635.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 2.51 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min).

Synthesis of N-((2-(5-(3-hydroxypropoxy) pyridin-2-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (750)

To to a stirring solution of compound 749 (30 mg, 0.047 mmol) in MeOH (5mL) under argon atmosphere was added p-Toluenesulfonic acid (4 mg, 0.023mmol) at RT and stirred for 3 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (1 mL) and pH was neutralized with aqueous saturated Na₂CO₃solution and extracted with 5% MeOH/EtOAc (2×1 mL). The combined organicextracts were dried over sodium sulfate and concentrated vacuo to affordcompound 750 (20 mg, 76%) as an off-white solid. TLC: 10% MeOH/EtOAc(R_(f): 0.5); ¹H NMR (DMSO-d₆, 400 MHz): δ 11.54 (br s, 1H), 9.52-9.44(m, 1H), 8.31 (d, J=3.1 Hz, 1H), 8.09-7.97 (m, 3H), 7.95-7.77 (m, 4H),7.54 (dd, J=8.7, 2.9 Hz, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.18-7.07 (m, 2H),4.69 (d, J=5.5 Hz, 1H), 4.63-4.59 (m, 1H), 4.24-4.14 (m, 2H), 3.60-3.56(m, 1H), 1.94-1.86 (m, 2H);

Synthesis of 3-((6-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b, f][1,4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) pyridin-3-yl) oxy)propyl methane sulfonate (751)

To a stirring solution of compound 750 (220 mg, 0.40 mmol) in CH₂Cl₂ (10mL) under inert atmosphere were added triethylamine (0.11 mL, 0.80 mmol)and methanesulfonyl chloride (0.04 mL, 0.60 mmol) at 0-5° C.; warmed toRT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with CH₂Cl₂(5 mL) and washed with water (2×5 mL). The organic extract was driedover sodium sulfate, filtered and concentrated in vacuo to affordcompound 751 (200 mg, crude) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂(R_(f): 0.3); LC-MS: 27.24%; 629.0 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 2.21 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-((2-(5-(3-(dimethylamino) propoxy) pyridin-2-yl)thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11011)

To a stirring solution of compound 751 (200 mg, 0.31 mmol) under argonatmosphere was added dimethyl amine (7 mL) in a sealed tube. Thereaction mixture was heated to 60° C. and stirred for 16 h. The reactionwas monitored by TLC; after completion the reaction the volatiles wereremoved in vacuo to obtain the crude. The crude was purified throughbasic alumina column chromatography using 2% MeOH/CH₂Cl₂ to afford 11011 (20 mg, 11%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f):0.1); ¹H NMR (DMSO-d₆, 400 MHz): δ 11.49 (br s, 1H), 9.45 (t, J=5.7 Hz,1H), 8.28 (d, J=2.6 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.03-7.95 (m, 3H),7.93-7.85 (m, 3H), 7.84-7.79 (m, 1H), 7.77 (s, 1H), 7.51 (dd, J=8.8, 2.9Hz, 1H), 4.67 (d, J=5.6 Hz, 2H), 4.13 (t, J=6.4 Hz, 2H), 2.40 (t, J=7.1Hz, 2H), 2.17 (s, 6H), 1.92-1.85 (m, 2H); LC-MS: 98.18%; 578.1 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.78 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):96.44%; (column; X select CSH C-18 (150×4.6 mm, 3.5 μm); RT 5.39 min.0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent: ACN:Water).

Synthesis of 11006, 11007, 11007-A & 11067

Synthesis of tert-butyl (3-bromopropyl) carbamate (753)

To a stirring solution of 3-bromopropan-1-amine hydrobromide 752 (20 g,91.35 mmol) in CH₂Cl₂ (200 mL) under inert atmosphere were addedBoc-anhydride (39.80 g, 182.15 mmol), diisopropylethylamine (75 mL,135.05 mmol) at 0° C.; warmed to RT and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was diluted with water (500 mL) and extracted with CH₂Cl₂ (2×500mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel flash column chromatography using 5-20%EtOAc/hexanes to afford compound 753 (15 g, 68%) as colorless liquid.TLC: 30% EtOAc/hexanes (R_(f): 0.8); ¹H NMR (DMSO-d₆, 400 MHz): δ 6.88(br s, 1H), 3.50 (t, J=6.6 Hz, 2H), 3.09-2.98 (m, 2H), 1.91 (p, J=6.7Hz, 2H), 1.38 (s, 9H); LC-MS (Agilent 6310 Ion Trap): 91.42%; 138.4(M⁺+1) (Des Boc) (Column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 3.78min. 2.5 mM Aq. NH₄OAc: ACN, 0.8 mL/min).

Synthesis of S-(3-((tert-butoxycarbonyl) amino) propyl) ethanethioate(755)

To a stirring solution of compound 753 (15 g, 63.29 mmol) in acetone(250 mL) under inert atmosphere was added potassium thioacetate 754 (7.2g, 63.29 mmol) at RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith water (250 mL) and extracted with EtOAc (2×250 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to afford compound 755 (10 g, crude) as colorlesssyrup. TLC: 30% EtOAc/hexanes (R_(f): 0.2); ¹H NMR (400 MHz, DMSO-d₆): δ6.82 (br s, 1H), 2.94 (q, J=6.6 Hz, 2H), 2.80 (t, J=7.2 Hz, 2H), 2.31(s, 3H), 1.60 (p, J=7.1 Hz, 2H), 1.37 (s, 9H);

Synthesis of tert-butyl (3-mercaptopropyl) carbamate (756)

To a stirring solution of compound 755 (10 g, crude) in MeOH (100 mL)under inert atmosphere was added potassium carbonate (17.76 g, 128.57mmol) portionwise for 15 min at 0° C.; warmed to RT and stirred for 2 h.The reaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with filtered through celite. The filtratewas concentrated in vacuo to afford crude compound 756 (7 g) as palebrown syrup. The crude was carried forward for next step without furtherpurification. TLC: 30% EtOAc/hexanes (R_(f): 0.7);

Synthesis of tert-butyl (3-((4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenyl) thio) propyl) carbamate (11007-A)

To a stirring solution of compound 538 (4 g, 7.21 mmol) in 1, 4-dioxane(40 mL) were added tert-butyl (3-mercaptopropyl) carbamate 756 (4.14 g,21.64 mmol) cesium carbonate (7.05 g, 21.66 mmol) and potassium iodide(1.19 g, 7.22 mmol) at RT and purged under argon atmosphere for 15 min.To this were added Pd₂(dba)₃ (661 mg, 0.72 mmol), Xantphos (292 mg, 0.50mmol) purged under argon atmosphere for 5 min; heated to 110° C. andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was filtered through celite. Thefiltrate was concentrated in vacuo to obtain the crude. The crude waspurified through silicagel flash column chromatography using 1-5%MeOH/CH₂Cl₂. The obtained compound was triturated with 5% MeOH/CH₂Cl₂ (2mL), n-pentane (5 mL) and further purified by preparative HPLCpurification to afford 11007-A (130 mg, 3%) as white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.4). ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.50 (br s, 1H),9.46 (t, J=5.7 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.98 (dd, J=7.8, 1.2 Hz,2H), 7.90 (td, J=7.5, 1.4 Hz, 1H), 7.87-7.84 (m, 2H), 7.84-7.77 (m, 4H),7.36 (d, J=8.5 Hz, 2H), 6.89 (t, J=4.7 Hz, 1H), 4.68 (d, J=5.5 Hz, 2H),3.07-2.96 (m, 4H), 1.70 (p, J=6.9 Hz, 2H), 1.36 (s, 9H); LC-MS: 95.07%;663.1 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 3.28min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8 mL/min);HPLC (purity): 95.22%; (column; X-select CSH-C18 (150×4.6 mm, 3.5 μm);RT 10.62 min. 0.05% TFA+5% ACN:ACN: +5% 0.05% ACN; 1.0 mL/min, Diluent:DMSO:ACN:water).

Synthesis of N-((2-(4-((3-aminopropyl) thio) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (11007)

To a stirring solution of 11007-A (200 mg, 0.30 mmol) in CH₂Cl₂ (20 mL)under inert atmosphere was added 4 N HCl in 1, 4-dioxane (2 mL) at 0°C.; warmed to RT and stirred for 4 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were removed in vacuo toafford 11007 (160 mg, 88%; HCl salt) as an off-white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.53 (s, 1H),9.50 (t, J=5.7 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.98 (dd, J=7.6, 1.1 Hz,2H), 7.94-7.74 (m, 10H), 7.45-7.38 (m, 2H), 4.68 (d, J=5.6 Hz, 2H), 3.12(t, J=7.2 Hz, 2H), 2.97-2.83 (m, 2H), 1.88 (p, J=7.3 Hz, 2H); LC-MS:95.89%; 566.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.88 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 96.17%; (column; X-select CSH C-18 (150×4.6 mm,3.5 μm); RT 5.95 min. 0.05% TFA (Aq)+5% ACN: ACN+5% 0.5% TFA (Aq); 1.0mL/min, Diluent: ACN:water).

Synthesis of N-((2-(4-((3-(dimethylamino) propyl) thio)phenyl)thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11006)

To a stirring solution of 11007 (130 mg, 0.21 mmol) in MeOH (10 mL)under inert atmosphere were added paraformaldehyde (32 mg, 1.08 mmol)and sodium cyanoborohydride (68 mg, 1.08 mmol) at 0° C.; warmed to RTand stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(50 mL) and extracted with 10% MeOH/CH₂Cl₂ (2×50 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 1-4% MeOH/CH₂Cl₂. Thecompound obtained was titurated with 5% MeOH/CH₂Cl₂ (5 mL) to afford11006 (20 mg, 15%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f):0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.51 (br s, 1H), 9.46 (t, J=5.4 Hz,1H), 8.06 (d, J=8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.84 (m, 3H),7.84-7.77 (m, 4H), 7.38 (d, J=8.5 Hz, 2H), 4.68 (d, J=5.3 Hz, 2H), 3.03(t, J=7.2 Hz, 2H), 2.38 (t, J=6.3 Hz, 2H), 2.16 (s, 6H), 1.73 (p, J=6.9Hz, 2H); LC-MS: 98.35%; 593.1 (M⁺+1); (Column; X-select CSH C-18(150×4.6 mm, 3.5 μm); RT 1.89 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.0 mL/min); HPLC (purity): 97.97%; (column; X-select CSH C-18(150×4.6 mm, 3.5 μm); RT 6.45 min. 0.05% TFA (Aq)+5% ACN: ACN+5% 0.5%TFA (Aq); 1.0 mL/min, Diluent: ACN:water).

Synthesis of N-((2-(4-((3-acetamidopropyl) thio) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11067)

To a stirring solution of 11007 (35 mg, 0.058 mmol) in THF:H₂O (4:2, 2mL) were added sodium carbonate (30 mg, 0.29 mmol), acetyl chloride(0.012 mL, 0.17 mmol) at 0° C.; warmed to RT and stirred for 2 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (50 mL) and extracted with EtOAc(2×100 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 3%MeOH/CH₂Cl₂ to afford 11067 (15 mg, 43%) as white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.6); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.51 (br s, 1H),9.46 (t, J=5.6 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.98 (td J=7.5, 1.1 Hz,2H), 7.93-7.85 (m, 4H), 7.84-7.77 (m, 4H), 7.37 (d, J=8.5 Hz, 2H), 4.68(d, J=5.5 Hz, 2H), 3.19-3.10 (m, 2H), 3.02 (t, J=7.2 Hz, 2H), 1.79 (s,3H), 1.71 (p, J=6.9 Hz, 2H); LC-MS: 97.37%; 607.1 (M⁺+1); (column;Ascentis Express C-18, (50×3.0 mm, 2.7 μm); RT 2.14 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.83%;(column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 8.14 min. 0.05% TFA(Aq)+5% ACN: ACN+5% 0.5% TFA (Aq); 1.0 mL/min, Diluent: ACN:water).

Synthesis of 11063

Synthesis of 3-((4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b, f][1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenyl) thio)propyl methanesulfonate (757)

To a stirring solution of 1 1063-A (500 mg, 0.88 mmol) in THF: CH₂Cl₂(1:1, 20 mL) under inert atmosphere were added triethylamine (1.2 mL,8.84 mmol), methanesulfonyl chloride (0.36 mL, 4.40 mmol) at 0° C.;warmed to RT and stirred for 16 h. The reaction was in monitored by TLC;after completion of the reaction, the reaction mixture was diluted withCH₂Cl₂ (100 mL) and washed with 10% sodium bicarbonate solution (50 mL).The organic extract was dried over sodium sulfate, filtered andconcentrated in vacuo to afford mixture of mono and di-compound 757 (1.4g) as brown thick syrup. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.7, 0.8); LC-MS:39.97%; 644.0 (M⁺+1) (monomesylated mass), 42.82%; 722.0 (M⁺+1)(dimesylated mass); (column; Ascentis Express C-18, (50×3.0 mm, 2.7 μm);RT: 2.49, 0.58 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min);

Synthesis of N-((2-(4-((3-(diethylamino) propyl) thio) phenyl)thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11063)

To a stirring solution of 3-((4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenyl) thio) propyl methanesulfonate 1 (120 mg, mixtureof compounds) in THF (1 mL) in a sealed tube was added diethylamine 387(1 mL, 8 vol) at RT and heated to 75° C. and stirred for 16 h. Thereaction was monitored by TLC; after completion the volatiles wereremoved in vacuo to obtain the crude. The crude was purified throughsilica gel (100-200 mesh) column chromatography using 4-5% MeOH/CH₂Cl₂to afford 11063 (15 mg, 13%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f). 0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.51 (br s, 1H), 9.46 (t,J=5.6 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.74 (m,7H), 7.37 (d, J=8.4 Hz, 2H), 4.68 (d, J=5.4 Hz, 2H), 3.04 (t, J=7.0 Hz,2H), 2.52-2.40 (m, 6H), 1.70 (quin, J=7.0 Hz, 2H), 0.94 (t, J=7.1 Hz,6H); LC-MS: 97.40%; 621.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0mm, 2.7 μm); RT 2.80 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min). HPLC (purity): 98.67%; (column; X select CSH C-18 (150×4.6mm, 3.5 μm); RT 6.14 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0mL/min, Diluent: water:DMSO:ACN).

Synthesis of 11064

Synthesis of N-((2-(4-((3-(tert-butylamino) propyl) thio) phenyl)thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide TFA Salt (11064)

To a stirring solution of compound 757 (300 mg, mixture) in DMF (8 mL)under inert atmosphere was added potassium carbonate (128 mg, 0.93mmol), 2-methylpropan-2-amine 469 (0.46 mL, 4.65 mmol) in a sealed tubeat RT; heated to 80° C. and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasdiluted with water (100 mL) and extracted with EtOAc (2×50 mL). Thecombined organic extracts were dried over sodium sulfate andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 2-5% MeOH/CH₂Cl₂ andfurther purified by preparative HPLC purification to afford 11064 (25mg, 9%) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.47 (t, J=5.8 Hz, 1H), 8.29-8.16(m, 2H), 8.05 (d, J=8.3 Hz, 1H), 8.00-7.94 (m, 2H), 7.89 (td, J=7.5, 1.6Hz, 1H), 7.87-7.77 (m, 5H), 7.42 (d, J=8.7 Hz, 2H), 4.67 (d, J=5.4 Hz,2H), 3.13 (t, J=7.2 Hz, 2H), 3.04-2.94 (m, 2H), 1.91-1.83 (m, 2H), 1.24(s, 9H); LC-MS: 98.77%; 621.1 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 1.97 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min); HPLC (purity): 99.27%; (column; X select CSH C-18(150×4.6 mm, 3.5 μm); RT 6.29 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA;1.0 mL/min, Diluent: ACN: DMSO).

Synthesis of 11065

Synthesis of 11-oxo-N-((2-(4-((3-(piperidin-1-yl) propyl) thio) phenyl)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11065)

To a stirring solution of 3-((4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenyl) thio) propyl methanesulfonate 757 (300 mg, mixtureof compounds) in THF (5 mL) in a sealed tube was added piperidine 472 (2mL, 6.6 vol) at RT and heated to 70° C. and stirred for 16 h. Thereaction was monitored by TLC; after completion the volatiles wereremoved in vacuo to obtain the crude. The crude was either purifiedthrough basic alumina column chromatography using 1-2% MeOH/CH₂Cl₂ toobtain the crude. The crude was diluted with EtOAc (50 mL), washed withwater (50 mL). The organic extract was dried over sodium sulfate,filtered and concentrated in vacuo and triturated with EtOAc (5 mL) toafford 11065 (20 mg, 7%) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂(R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.51 (br s, 1H), 9.46 (t,J=5.6 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.98 (td, J=1.3, 7.5, 1.3 Hz,2H), 7.90 (td, J=7.4, 1.4 Hz, 1H), 7.87-7.76 (m, 6H), 7.38 (d, J=8.5 Hz,2H), 4.68 (d, J=5.6 Hz, 2H), 3.03 (t, J=7.2 Hz, 2H), 2.42-2.21 (m, 6H),1.81-1.69 (m, 2H), 1.77-1.72 (m, 2H), 1.52-1.44 (m, 4H), 1.42-1.29 (m,2H); LC-MS: 98.99%; 633.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0mm, 2.7 μm); RT 1.98 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min). HPLC (purity): 96.51%; (column; X select CSH C-18 (150×4.6mm, 3.5 μm); RT 6.17 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0mL/min, Diluent: water:DMSO:ACN).

Synthesis of 11066

Synthesis of N-((2-(4-((3-morpholinopropyl) thio) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11066)

To a stirring solution of 3-((4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenyl) thio) propyl methanesulfonate 757 (300 mg, mixtureof compounds) in THF (5 mL) in a sealed tube was added morpholine (2 mL,6.6 vol) at RT and heated to 70° C. and stirred for 16 h. The reactionwas monitored by TLC; after completion the volatiles were removed invacuo to obtain the crude. The crude was purified through basic aluminacolumn chromatography using 1-2% MeOH/CH₂Cl₂ to obtain the crude. Thecrude was diluted with water (10 mL), washed with water (50 mL). Theorganic extract was dried over sodium sulfate and stirred for 16 h. Theobtained solid was filtered, washed with n-pentane (5 mL) and dried invacuo to afford 11066 (72 mg, 24%) as an off-white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.52 (s, 1H),9.46 (t, J=5.7 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.98 (td, J=7.5, 1.1 Hz,2H), 7.93-7.84 (m, 3H), 7.84-7.76 (m, 4H), 7.38 (d, J=8.4 Hz, 2H), 4.68(d, J=5.5 Hz, 2H), 3.55 (t, J=4.6 Hz, 4H), 3.05 (t, J=7.2 Hz, 2H), 2.32(d, J=4.0 Hz, 5H), 1.75 (p, J=7.0 Hz, 2H); LC-MS: 99.08%; 635.1 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.91 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity):99.03%; (column; X select CSH C-18 (150×4.6 mm, 3.5 μm); RT 5.91 min.0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent: ACN:water).

Synthesis of 11032, 11063-A, 11063-B

Synthesis of 3-((4-bromophenyl) thio) propan-1-ol (759)

To a stirring solution of 4-bromobenzenethiol 758 (5 g, 26.45 mmol) inTHF (100 mL) under argon atmosphere was added sodium hydride (60%, 1.9g, 79.16 mmol) portion wise for 10 min at 0° C.; warmed to RT andstirred for 1 h. To this was added 3-bromopropan-1-ol 384 (4.3 g, 31.74mmol) at 0° C.; warmed to RT and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas quenched with ice-cold water (50 mL) and extracted with EtOAc (2×150mL), washed with water (100 mL), brine (100 mL). The organic extract wasdried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 20% EtOAc/hexanes to afford compound 759 (4.5 g,69%) as colorless thick syrup. TLC: 30% EtOAc/hexanes (R_(f): 0.4);¹H-NMR (DMSO-d₆, 400 MHz): δ 7.48 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.7 Hz,2H), 4.55 (t, J=5.2 Hz, 1H), 3.51-3.45 (m, 2H), 3.00 (t, J=7.2 Hz, 2H),1.70 (p, J=6.7 Hz, 2H);

Synthesis of 3-((4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl) thio) propan-1-ol (760) (SAP-MA1623-71)

To a stirring solution of compound 759 (3 g, 12.14 mmol) in 1, 4-dioxane(90 mL) under inert atmosphere were added bispinacolato diboron (4.17 g,16.51 mmol), potassium acetate (3.6 g, 36.43 mmol) at RT and purgedunder argon atmosphere for 15 min; to this was added Pd(dppf)Cl₂.CH₂Cl₂(991 mg, 1.21 mmol) and purged under argon atmosphere for 5 min, heatedto 100° C. and stirred for 16 h. The reaction was monitored by TLC;after completion of the reaction, the volatiles were concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 10-30% EtOAc/hexanes to afford compound 760(4.7 g, 43%) as colorless syrup. TLC: 30% EtOAc/hexanes (R_(f): 0.3);¹H-NMR (DMSO-d₆, 400 MHz): δ 7.56 (d, J=8.3 Hz, 2H), 7.27 (d, J=8.3 Hz,2H), 4.55 (t, J=5.2 Hz, 1H), 3.51-3.45 (m, 2H), 3.01 (t, J=7.3 Hz, 2H),1.78-1.61 (m, 2H), 1.27 (s, 12H);

Synthesis of N-((2-(4-((3-hydroxypropyl) thio) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11063-A)

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide535 (2.5 g, 5.77 mmol) in 1, 4-dioxane: H₂O (2:1, 113 mL) were added 23-((4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) thio)propan-1-ol 760 (3.4 g, 11.54 mmol), sodium bicarbonate (1.94 g, 23.09mmol) and purged under argon atmosphere for 30 min. To this was addedPd(PPh₃)₄ (560 mg, 0.48 mmol) and purged under argon atmosphere for 5min at RT; heated to 90° C. and stirred for 16 h. The reaction wasmonitored by TLC and LC-MS; after completion the reaction, the reactionmixture was diluted with water (100 mL) and extracted with EtOAc (2×100mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 1-6%MeOH/CH₂Cl₂, triturated with 5% MeOH/CH₂Cl₂ (10 mL), n-pentane (20 mL)and dried in vacuo to afford 11063-A (3 g, 43%) as an off-white solid.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 11.51 (s,1H), 9.46 (t, J=5.8 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 8.02-7.95 (m, 2H),7.92-7.85 (m, 3H), 7.84-7.76 (m, 4H), 7.37 (d, J=8.7 Hz, 2H), 4.68 (d,J=5.6 Hz, 2H), 4.57 (t, J=5.2 Hz, 1H), 3.54-3.47 (m, 2H), 3.09-3.02 (m,2H), 1.78-1.70 (m, 2H); LC-MS: 94.81%; 566.1 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.30 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.73%; (column;X-Select CSH-C-18 (150×4.6 mm, 3.5 μm); RT 8.25 min. 0.05% TFA (Aq)+5%ACN: ACN+5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN: DMSO).

Synthesis of N-((2-(4-((3-hydroxypropyl) sulfonyl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11063-B)

To a stirring solution of 11063-A (200 mg, 0.35 mmol) in CH₂Cl₂ (10 mL)under argon atmosphere was added m-chloro perbenzoic acid (73 mg, 0.42mmol) at 0° C.; warmed to RT and stirred for 30 min. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with water (100 mL), aqueous ammonia (20 mL) and extractedwith 10% MeOH/CH₂Cl₂ (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 1-5% MeOH/CH₂Cl₂, triturated with 10% MeOH/CH₂Cl₂and dried in vacuo to afford 11063-B (60 mg, 28%) as an off-white solid.TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 11.65(br s, 1H), 9.62 (t, J=5.7 Hz, 1H), 8.24 (d, J=8.7 Hz, 2H), 8.16 (d,J=8.3 Hz, 1H), 8.11-8.04 (m, 4H), 8.03-7.90 (m, 5H), 4.82 (d, J=5.5 Hz,2H), 4.71 (t, J=5.3 Hz, 1H), 3.50 (q, J=6.1 Hz, 2H), 3.46-3.42 (m, 2H),1.83-1.73 (m, 2H); LC-MS: 98.25%; 596.1 (M−1)⁺; (column; Kinetex EVOC-18 (50×3.0 mm, 2.6 um); RT 2.28 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5%2.5 mM Aq.NH₄OOCH, 0.8 mL/min); HPLC (purity): 98.97%; (column; X-SelectCSH-C-18 (150×4.6 mm, 3.5 μm); RT 8.25 min. 0.05% TFA (Aq)+5% ACN:ACN+5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: ACN:H₂O:DMSO).

Synthesis of 3-((4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b, f][1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenyl) sulfonyl)propyl methanesulfonate (761)

To a stirring solution of N-((2-(4-((3-hydroxypropyl) sulfonyl) phenyl)thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide 11063-B (350 mg, 0.58 mmol) inTHF: CH₂Cl₂ (1:1, 16 mL) under inert atmosphere were added triethylamine(6 mL, 41.58 mmol), methanesulfonyl chloride (1.2 mL, 14.73 mmol) at 0°C.; warmed to RT and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith CH₂Cl₂ (100 mL) and washed with water (75 mL). The organic extractwas dried over sodium sulfate, filtered and concentrated in vacuo toafford crude compound 761 (450 mg) as colorless liquid. The crude wascarried forward for next step without further purification. TLC: 30%EtOAc/hexanes (R_(f). 0.8);

Synthesis of N-((2-(4-((3-azidopropyl) sulfonyl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (762)

To a stirring solution of compound 761 (450 mg, crude) in DMF (5 mL)under inert atmosphere was added sodium azide (129 mg, 1.99 mmol) at RTand stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with EtOAc(100 mL) washed with water (100 mL), brine (50 mL). The organic extractwas dried over sodium sulphate, filtered and concentrated in vacuo toafford crude compound 762 (320 mg) as colorless sticky solid. The crudewas carried forward for next step without further purification TLC: 20%EtOAc/hexanes (R_(f): 0.4);

Synthesis of N-((2-(4-((3-aminopropyl) sulfonyl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide TFA salt (11032)

To a stirring solution of compound 762 (320 mg, crude) in THF:H₂O (4:1,10 mL) was added triphenyl phosphine (134 mg, 0.51 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction; the volatiles were removed in vacuo to obtain the crudeamine (250 mg crude). The crude was purified by preparative HPLCpurification to afford 11032 (15 mg, 4.6%) as an off-white solid. TLC:5% MeOH/CH₂Cl₂ (R_(f). 0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ 11.53 (s, 1H),9.53 (t, J=5.8 Hz, 1H), 8.17 (d, J=8.7 Hz, 2H), 8.06 (d, J=8.3 Hz, 1H),8.00-7.89 (m, 6H), 7.88-7.79 (m, 3H), 7.63 (br s, 3H), 4.72 (d, J=5.5Hz, 2H), 3.50-3.44 (m, 2H), 2.91-2.83 (m, 2H), 1.87-1.80 (m, 2H); LC-MS:99.29%; 597.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.79 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min). HPLC (purity): 98.76%; (column; X select CSH C-18 (150×4.6 mm,3.5 μm); RT 5.50 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min,Diluent: DMSO:ACN:water).

Synthesis of 11033

Synthesis of N-((2-(4-((3-(dimethylamino) propyl) sulfonyl) phenyl)thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide TFA Salt (11033)

To a stirring solution of 3-((4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenyl) sulfonyl) propyl methanesulfonate 761 (250 mg,0.37 mmol) in DMF (1 mL) in a sealed tube was added 2 M dimethylamine inTHF (20 mL, 31.11 mmol) at RT and heated to 70° C. and stirred for 16 h.The reaction was monitored by TLC; after completion the volatiles wereremoved in vacuo to obtain the crude. The crude was either purifiedthrough silica gel column chromatography using 5-10% MeOH/CH₂Cl₂ andfurther purified by preparative HPLC purification. The compound obtainedwas lyophilized for 16 h to afford 11033 (20 mg, 9%) as an off-whitesolid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ11.53 (s, 1H), 9.53 (t, J=5.8 Hz, 1H), 9.29 (br s, 1H), 8.17 (d, J=8.5Hz, 2H), 8.06 (d, J=8.3 Hz, 1H), 8.01-7.94 (m, 4H), 7.93-7.80 (m, 5H),4.72 (d, J=5.6 Hz, 2H), 3.47-3.42 (m, 2H), 3.11 (t, J=6.8 Hz, 2H), 2.74(s, 6H), 1.99-1.89 (m, 2H); LC-MS: 97.65%; 624.1 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.79 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 99.70%;(column; X select CSH C-18 (150×4.6 mm, 3.5 μm); RT 5.59 min. 0.05%TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent: DMSO:ACN:water)

Synthesis of 1654

Synthesis of tert-butyl (4-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzyl) carbamate (763)

To a stirring solution of tert-butyl (4-bromobenzyl) carbamate 762 (1 g,3.49 mmol) in DMSO (20 mL) under inert atmosphere were addedbispinacolato diboron (1.06 g, 4.19 mmol), potassium acetate (1.02 g,10.48 mmol) at RT and stirred under argon atmosphere for 30 min, addedPd(dppf)₂Cl₂ (255 mg, 0.35 mmol) and heated to 90-100° C. and stirredfor 16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was diluted with water (100 mL) extractedwith EtOAc (2×100 mL). The combined organic extracts were dried oversodium sulphate, filtered and concentrated in vacuo obtain the crude.The crude was purified through silica gel column chromatography using10% EtOAc/hexanes to afford compound 763 (500 mg, 43%). TLC: 20%EtOAc/hexanes (R_(f). 0.8); ¹H NMR (DMSO-d₆, 400 MHz): δ 7.62 (d, J=7.8Hz, 2H), 7.38 (t, J=5.5 Hz, 1H), 7.24 (d, J=7.9 Hz, 2H), 4.13 (d, J=6.2Hz, 2H), 1.39 (s, 9H), 1.28 (s, 12H).

Synthesis of tert-butyl (4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) benzyl) carbamate (764)

To a stirring solution of compound 763 (150 mg, 0.34 mmol) in 1, 2dimethoxy ethane: H₂O (4:1, 5 mL) were added (4-hydroxyphenyl) boronicacid 762 (230 mg, 0.69 mmol), sodium carbonate (128 mg, 1.21 mmol) andpurged under argon atmosphere for 30 min. To this was added Pd(PPh₃)₄(40 mg, 0.034 mmol) at RT; heated to 100° C. and stirred for 16 h. Thereaction was monitored by TLC; after completion the reaction mixture wasdiluted with water (100 mL) and extracted with 10% MeOH/CH₂Cl₂ (2×100mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silica gel column chromatography using 3% MeOH/CH₂Cl₂to afford compound 764 (70 mg, 33%) as white solid. TLC: 5% MeOH/CH₂Cl₂(R_(f): 0.3); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.52 (s, 1H), 9.47 (t, J=5.7Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.98 (dd, J=7.5, 1.5 Hz, 2H), 7.90 (td,J=7.5, 1.5 Hz, 1H), 7.87-7.80 (m, 5H), 7.78 (s, 1H), 7.43 (t, J=5.7 Hz,1H), 7.32 (d, J=8.3 Hz, 2H), 4.68 (d, J=5.5 Hz, 2H), 4.15 (d, J=6.1 Hz,2H), 1.39 (s, 9H).

Synthesis of N-((2-(4-(aminomethyl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1654)

To a stirring solution of compound 764 (65 mg, 0.10 mmol) in CH₂Cl₂ (2mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (1 mL) at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was washed with EtOAc (2×5 mL) anddried in vacuo to afford 1654 (40 mg, 69%) as an off-white solid. TLC:10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ 11.54 (s,1H), 9.53 (t, J=5.8 Hz, 1H), 8.31 (br s, 3H), 8.06 (d, J=8.1 Hz, 1H),8.01-7.88 (m, 5H), 7.87-7.82 (m, 4H) 7.57 (d, J=8.1 Hz, 2H), 4.69 (d,J=5.5 Hz, 2H), 4.07 (q, J=5.8 Hz, 2H); LC-MS: 96.02%; 505.0 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.78 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):96.27%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 5.43 min.ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0 mL/min, Diluent:ACN:water).

Synthesis of 1839

Synthesis of (2-bromophenethoxy) (tert-butyl) dimethylsilane (766)

To a stirring solution of 2-(2-bromophenyl) ethan-1-ol 765 (2 g, 9.95mmol) in CH₂Cl₂ (50 mL) under inert atmosphere was added imidazole (1.35g, 19.85 mmol) at 0° C. and stirred for 10 min, followed by addition ofTBDMS-Cl (1.79 g, 11.93 mmol) at 0° C.; warmed to RT and stirred for 16h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was diluted with water (50 mL) and extracted withCH₂Cl₂ (3×50 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo to obtain the crude. Thecrude was purified through silica gel column chromatography using 2-5%EtOAc/hexanes to afford compound 766 (3 g, 96%) as colorless liquid.TLC: 10% EtOAc/hexanes (R_(f): 0.8); ¹H-NMR (DMSO-d₆, 500 MHz): δ 7.57(d, J=8.1 Hz, 1H), 7.36-7.28 (m, 2H), 7.16 (t, J=7.5 Hz, 1H), 3.78 (t,J=6.8 Hz, 2H), 2.90 (t, J=6.7 Hz, 2H), 0.82 (s, 9H), 0.06 (s, 6H).

Synthesis of tert-butyldimethyl(2-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenethoxy) silane (767)

To a stirring solution of compound 766 (1 g, 3.18 mmol) in 1, 4-dioxane(30 mL) under argon atmosphere were added bispinacolato diboron (1.20 g,4.74 mmol), potassium carbonate (1.31 g, 9.49 mmol) at RT and purgedargon atmosphere for 5 min, added Pd(dppf)Cl₂ (232 mg, 0.31 mmol) andheated to reflux and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was filteredthrough celite. The filtrate was concentrated in vacuo to obtain thecrude. The crude was purified through silica gel flash columnchromatography using 5-20% EtOAc/hexanes to afford compound 767 (300 mg,26%) as pale yellow liquid. TLC: 2% EtOAc/hexanes (R_(f): 0.5); LC-MS:93.59%; 363.2 (M⁺+1); (column; X-select CSH C-18 (50×3.0 mm, 2.5 μm); RT5.19 min. 2.5 mM NH₄OOCH (Aq)+5% ACN: ACN+5% 2.5 mM NH₄OOCH (Aq); 0.8mL/min).

Synthesis of N-((2-(2-(2-((tert-butyldimethylsilyl) oxy) ethyl) phenyl)thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (768)

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide535 (200 mg, 0.46 mmol) in 1, 2-dimethoxy ethane: H₂O (3:1, 26 mL) underinert atmosphere were added compound 767 (334 mg, 0.92 mmol), sodiumcarbonate (147 mg, 1.38 mmol) in a sealed tube at RT and purged underargon atmosphere for 15 min, added Pd(dppf)Cl₂ (33.76 mg, 0.046 mmol)and purged under argon atmosphere for 10 min and heated to 100° C. andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was filtered through celite and thefiltrate was concentrated in vacuo to obtain the crude. The crude waspurified through silica gel flash column chromatography using 2%MeOH/CH₂Cl₂ to afford compound 768 (150 mg, crude) as pale yellowliquid. TLC: % MeOH/CH₂Cl₂ (R_(f): 0.4);

Synthesis of N-((2-(2-(2-hydroxyethyl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (1839)

To a stirring solution of compound 768 (150 mg, 0.23 mmol) in CH₂Cl₂ (5mL) under inert atmosphere was added trifluoroacetic acid (0.3 mL) at 0°C.; warmed to RT and stirred for 4 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwashed with water (75 mL) and extracted with 5% MeOH/CH₂Cl₂ (3×50 mL),The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to obtain the crude. The crude was purified bypreparative HPLC purification to afford 1839 (80 mg, 33% over 2 steps)as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H-NMR(DMSO-d₆, 400 MHz): δ 11.51 (s, 1H), 9.48 (t, J=5.6 Hz, 1H), 8.06 (d,J=8.3 Hz, 1H), 7.98 (td, J=7.7, 1.1 Hz, 2H), 7.93-7.80 (m, 5H), 7.53 (d,J=7.5 Hz, 1H), 7.44-7.36 (m, 2H), 7.34-7.26 (m, 1H), 4.71 (d, J=5.6 Hz,2H), 4.65-4.56 (m, 1H), 3.56 (t, J=7.0 Hz, 2H), 3.04 (t, J=7.0 Hz, 2H);LC-MS: 95.17%; 520.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 2.14 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 95.97%; (column; X-select CSH C-18 (150×4.6 mm,3.5 μm); RT 7.82 min. 0.05% TFA (Aq)+5% ACN: ACN+5% 0.05% TFA (Aq): 1.0mL/min, Diluent: DMSO:ACN:water).

Synthesis of 1842

Synthesis of 2-(2-bromophenyl) ethan-1-amine (770)

To a stirring solution of 2-(2-bromophenyl) acetonitrile 769 (1 g, 5.10mmol) in THF (25 mL) under inert atmosphere was added borane dimethylsulfide complex (3.06 mL, 15.30 mmol, 5.0 M) dropwise for 5 min at RTand heated to 80° C. and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was quenchedwith MeOH (5 mL). To this was added 2 N HCl (20 mL) and refluxed for 1h. The reaction mixture was basified using 10% aqueous NaHCO₃ solution(50 mL) and extracted with EtOAc (2×100 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to afford compound 770 (750 mg, crude) as colorless oil. The crudewas carried forward for next step without further purification. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.1);

Synthesis of tert-butyl (2-bromophenethyl) carbamate (771)

To a stirring solution of compound 770 (750 mg, 3.75 mmol) in THF:H₂O(4:1. 10 mL) were added NaHCO₃ (788 mg, 9.37 mmol) and Boc-anhydride(1.63 g, 7.50 mmol) at RT and stirred for 5 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with water (30 mL) and extracted with EtOAc (2×100 mL). Thecrude was purified through silica gel column chromatography using 10%EtOAc/hexanes to afford compound 771 (600 mg, 53%) as thick syrup. TLC:30% EtOAc/hexanes (R_(f): 0.8). ¹H-NMR (DMSO-d₆, 500 MHz): δ 7.57 (d,J=8.1 Hz, 1H), 7.35-7.26 (m, 2H), 7.19-7.12 (m, 1H), 6.91 (t, J=5.5 Hz,1H), 3.16 (q, J=6.7 Hz, 2H), 2.82 (t, J=7.2 Hz, 2H), 1.36 (s, 9H).

Synthesis of tert-butyl (2-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenethyl) carbamate (772)

To a stirring solution of compound 771 (600 mg, 2.00 mmol) in 1,4-dioxane (20 mL) under inert atmosphere were added bispinacolatodiboron (556 mg, 2.20 mmol), potassium acetate (686 mg, 7.00 mmol) RTand purged argon atmosphere for 30 min, added Pd(dppf)Cl₂ (146 mg, 0.20mmol) and heated to 100° C. and stirred for 6 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas filtered through celite, washed with EtOAc (2×50 mL). The filtratewas concentrated in vacuo to afford compound 772 (600 mg). TLC: 10%EtOAc/hexanes (R_(f): 0.8); LC-MS: 66.71%; 248.1 (M⁺+1) (Des Boc);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 3.17 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of tert-butyl (2-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenethyl) carbamate (773)

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide535 (150 mg, 0.34 mmol) in 1, 2-dimethoxy ethane:H₂O (4:1, 10 mL) underinert atmosphere were added compound 772 (300 mg, 0.86 mmol), sodiumcarbonate (128 mg, 1.21 mmol) at RT and purged under argon atmospherefor 30 min; added Pd(dppf)Cl₂ (25 mg, 0.034 mmol) and heated to 110° C.and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture the volatiles wereremoved in vacuo to obtain the crude. The crude was purified throughsilica gel column chromatography using 2% MeOH/CH₂Cl₂ to afford compound773 (60 mg, 28%) as brown syrup. TLC: 2% MeOH/CH₂Cl₂ (R_(f): 0.4);¹H-NMR (DMSO-d₆, 500 MHz): δ 11.52 (s, 1H), 9.48 (t, J=5.8 Hz, 1H), 8.06(d, J=8.1 Hz, 1H), 8.00-7.96 (m, 2H), 7.93-7.80 (m, 5H), 7.55 (d, J=7.2Hz, 1H), 7.41-7.37 (m, 1H), 7.35-7.28 (m, 2H), 6.83 (t, J=4.6 Hz, 1H),4.71 (d, J=5.8 Hz, 2H), 3.14 (q, J=6.3 Hz, 2H), 3.03-2.97 (m, 2H), 1.30(s, 9H); LC-MS: 97.49%; 619.1 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 2.55 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min).

Synthesis of N-((2-(2-(2-aminoethyl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1842)

To a stirring solution of compound 773 (60 mg, 0.097 mmol) in CH₂Cl₂ (5mL) was added 4 N HCl in 1, 4-dioxane (1 mL) under argon atmosphere at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude washed with EtOAc (5 mL) and dried in vacuo to affordcompound 1842 (35 mg, 65%; HCl salt) as white solid. TLC: 5% MeOH/CH₂Cl₂(R_(f). 0.1); ¹H-NMR (DMSO-d₆, 400 MHz): δ 11.54 (s, 1H), 9.56 (t, J=5.8Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.98 (td, J=7.4, 1.3 Hz, 2H), 7.94-7.82(m, 8H), 7.61 (dd, J=7.6, 0.9 Hz, 1H), 7.50-7.35 (m, 3H), 4.72 (d, J=5.6Hz, 2H), 3.21-3.13 (m, 2H), 3.12-3.02 (m, 2H); LC-MS: 99.26%; 519.1(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.85 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min). HPLC(purity): 98.26%; (column; X-select CSH-C18 (150×4.6 mm, 3.5 μm); RT6.21 min. 0.05% TFA (Aq)+5% ACN: ACN+5% 0.05% TFA (Aq); 1.0 mL/min,Diluent: DMSO:ACN:water).

Synthesis of 1841

Synthesis of tert-butyl (2-bromobenzyl) carbamate (775)

To a stirring solution of (2-bromophenyl) methanamine 774 (2 g, 10.75mmol) in CH₂Cl₂ (20 mL) under inert atmosphere were added triethylamine(2.29 mL, 16.13 mmol) and Boc-anhydride (2.81 g, 12.89 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with water (50 mL) andextracted with CH₂Cl₂ (2×100 mL). The crude was purified through silicagel flash column chromatography using 5% EtOAc/hexanes to affordcompound 775 (2.8 g, 91%) as an off-white solid. TLC: 20% EtOAc/hexanes(R_(f): 0.8). ¹H NMR (400 MHz, DMSO-d₆): δ 7.58 (dd, J=1.0, 7.9 Hz, 1H),7.43 (br t, J=5.6 Hz, 1H), 7.41-7.35 (m, 1H), 7.28 (br d, J=7.4 Hz, 1H),7.20 (td, J=7.6, 1.8 Hz, 1H), 4.16 (d, J=6.1 Hz, 2H), 1.41 (s, 9H);

Synthesis of tert-butyl (2-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzyl) carbamate (776)

To a stirring solution of compound 775 (1 g, 3.49 mmol) in 1, 4-dioxane(20 mL) under argon atmosphere were added bispinacolato diboron (1.06 g,4.18 mmol), potassium acetate (1.03 g, 10.51 mmol) at RT and purgedargon atmosphere for 15 min, added Pd(dppf)Cl₂ (256 mg, 0.35 mmol) andheated to 100° C. and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was filteredthrough celite. The filtrate was concentrated in vacuo to obtain thecrude. The crude was purified through silica gel flash columnchromatography using 2-10% EtOAc/hexanes to afford compound 776 (700 mg,56%) as pale yellow liquid. TLC: 2% EtOAc/hexanes (R_(f): 0.5); ¹H NMR(400 MHz, DMSO-d₆): δ 7.65 (dd, J=7.3, 1.1 Hz, 1H), 7.44 (dt, J=7.5, 1.1Hz, 1H), 7.27-7.19 (m, 3H), 7.14 (br t, J=6.0 Hz, 1H), 4.38 (br d, J=6.1Hz, 2H), 1.40 (s, 9H), 1.31 (s, 12H); LC-MS: 74.04%; 332.3 (M⁺+1);column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 3.09 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);

Synthesis of tert-butyl (2-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) benzyl) carbamate (777)

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamide 5, 5-dioxide535 (200 mg, 0.46 mmol) in 1, 2-dimethoxy ethane:H₂O (4:1, 25 mL) underinert atmosphere were added compound 776 (200 mg, 0.55 mmol), sodiumcarbonate (147 mg, 1.38 mmol) in a sealed tube at RT and purged underargon atmosphere for 15 min, added Pd(PPh₃)₄ (53.30 mg, 0.046 mmol) andpurged under argon atmosphere for 10 min and heated to 120° C. andstirred for 6 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was filtered through celite and thefiltrate was concentrated in vacuo to obtain the crude. The crude waspurified through silica gel flash column chromatography using 2-5%MeOH/CH₂Cl₂ to afford compound 777 (150 mg, 54%) as an off-white solid.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); LC-MS: 93.68%; 605.1 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.57 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min).

Synthesis of N-((2-(2-(aminomethyl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride (1841)

To a stirring solution of compound 777 (150 mg, 0.24 mmol) in CH₂Cl₂ (10mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (1 mL) at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was triturated with diethyl ether(50 mL) and dried in vacuo to afford 1841 (65 g, 48%) as white solid.TLC: 5% EtOAc/hexanes (R_(f). 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ 11.48(br s, 1H), 9.56 (t, J=5.7 Hz, 1H), 8.33 (br s, 2H), 8.08 (d, J=8.3 Hz,1H), 8.02-7.96 (m, 2H), 7.94-7.78 (m, 6H), 7.64-7.59 (m, 1H), 7.58-7.52(m, 2H), 4.73 (d, J=5.5 Hz, 2H), 4.25 (s, 2H); LC-MS: 99.47%; 505.1(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.84 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min). HPLC(purity): 99.71%; (column; X-select CSH-C18 (150×4.6 mm, 3.5 μm); RT6.10 min. 0.05% TFA (Aq)+5% ACN: ACN+5% 0.05% TFA (Aq); 1.0 mL/min,Diluent: DMSO:ACN:water).

Synthesis of 11002-A, 11002 & 11004

Synthesis of 4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl) but-3-yn-1-olhydrochloride (778)

To a stirring solution of compound 464 (310 mg, 0.86 mmol) in CH₂Cl₂ (10mL) was added 4 N HCl in 1, 4-dioxane (5 mL) under inert atmosphere at0° C.; warmed to RT and stirred for 3 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo. The crude was triturated with EtOAc (5 mL), diethylether (5 mL)and dried in vacuo to afford compound 778 (280 mg, quantitative; HClsalt) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.1); LC-MS:94.71%; 258.9 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT1.48 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH, 0.8mL/min).

Synthesis of N-((2-(4-(4-hydroxybut-1-yn-1-yl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11002-A)

To a stirring solution of compound 92 (150 mg, 0.49 mmol) in CH₃CN (20mL) under argon atmosphere was added, 1-propylphosphonic acid cyclicanhydride (50% solution in EtOAc, 0.89 mL, 1.48 mmol),4-(4-(5-(aminomethyl) thiazol-2-yl) phenyl) but-3-yn-1-ol hydrochloride(160 mg, 0.54 mmol) at 0° C.; warmed to RT and stirred for 24 h. Thereaction was monitored by TLC; after completion of the reaction, thevolatiles were concentrated in vacuo. The residue was diluted with water(50 mL) and extracted with EtOAc (2×50 mL). The combined organicextracts were dried over sodium sulfate and concentrated in vacuo. Thecrude purified through silica gel column chromatography to afford11002-A (130 mg, 48%) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f):0.5); ¹H NMR (400 MHz, DMSO-d₆): δ 11.47 (brs, 1H), 9.48 (t, J=5.7 Hz,1H), 8.06 (d, J=8.3 Hz, 1H), 7.98 (dd, J=7.5, 1.4 Hz, 2H), 7.90 (td,J=7.5, 1.5 Hz, 1H), 7.87-7.79 (m, 6H), 7.47 (d, J=8.5 Hz, 2H), 4.90 (t,J=5.6 Hz, 1H), 4.69 (br d, J=5.6 Hz, 2H), 3.64-3.54 (m, 2H), 2.57 (t,J=6.8 Hz, 2H); LC-MS: 99.59%; 544.0 (M⁺+1); (column; Ascentis ExpressC18, (50×3.0 mm, 2.7 μm); RT 2.17 min. 0.025% Aq. TFA+5% ACN: ACN+5%0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.71%; (column; X-selectCSH C-18 (150×4.6 mm, 3.5 μm); RT 8.43 min. 0.05% TFA (Aq)+5% ACN:ACN+5% 0.05% TFA (Aq); 1.0 mL/min, Diluent: DMSO:ACN:water).

Synthesis of 4-(4-(5-((5, 5-dioxido-11-oxo-10, 11-dihydrodibenzo [b, f][1, 4] thiazepine-8-carboxamido) methyl) thiazol-2-yl) phenyl)but-3-yn-1-yl methanesulfonate (779)

To a stirring solution of 1 1002-A (650 mg, 1.19 mmol) in CH₂Cl₂ (50 mL)under inert atmosphere were added triethyl amine (0.2 mL, 2.39 mmol),methanesulfonyl chloride (0.11 mL, 1.43 mmol) at 0° C.; warmed to RT andstirred for 6 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was quenched with ice-cold water (50mL) and extracted with CH₂Cl₂ (2×75 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toafford crude compound 779 (800 mg) as colorless thick syrup. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.8); LC-MS: 52.47%; 622.0 (M⁺+1); 28.75%; 700.0(M⁺+1) (Dimesylated compound); (column; Ascentis Express C-18, (50×3.0mm, 2.7 μm); RT 2.38 min, 2.53 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min);

Synthesis of N-((2-(4-(4-azidobut-1-yn-1-yl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, 0.1] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (780)

To a stirring solution of compound 779 (800 mg, 1.27 mmol) in DMF (10mL) under inert atmosphere was added sodium azide (100 mg, 1.54 mmol) atRT and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(50 mL) and extracted with EtOAc (2×50 mL). The combined organicextracts were dried over sodium sulphate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 5% MeOH/CH₂Cl₂ to afford compound 780 (400mg) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f). 0.6); ¹H NMR (400MHz, DMSO-d₆): 11.51 (s, 1H), 9.48 (t, J=5.5 Hz, 1H), 8.06 (d, J=8.1 Hz,1H), 8.01-7.96 (m, 2H), 7.94-7.78 (m, 7H), 7.48 (d, J=8.1 Hz, 2H), 4.69(br d, J=5.8 Hz, 2H), 3.53 (t, J=6.4 Hz, 2H), 2.77 (t, J=6.4 Hz, 2H);

Synthesis of N-((2-(4-(4-aminobut-1-yn-1-yl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11002)

To a stirring solution of compound 780 (430 mg, 0.75 mmol) in THF:H₂O(4:1, 45 mL) was added triphenyl phosphine (238 mg, 0.90 mmol) at 0° C.;warmed to RT and stirred for 16 h. The reaction was monitored by TLC andLC-MS; after completion of the reaction; the reaction mixture wasquenched with water (50 mL) and extracted with 10% MeOH/CH₂Cl₂ (2×50mL). The combined organic extracts were dried over sodium sulphate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through basic alumina column chromatography using NH₄OH: MeOH:11002 (80 mg, 19%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f):0.1); ¹H NMR (400 MHz, DMSO-d₆): δ 9.48 (t, J=5.7 Hz, 1H), 8.05 (d,J=8.2 Hz, 1H), 7.98 (td, J=7.3, 0.9 Hz, 2H), 7.94-7.75 (m, 7H), 7.48 (d,J=8.4 Hz, 2H), 5.47-5.04 (m, 2H), 4.69 (d, J=5.5 Hz, 2H), 2.75 (t, J=6.8Hz, 2H) 2.61-2.50 (m, 1H), 2.49-2.41 (m, 1H); LC-MS: 96.45%; 543.0(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.85 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC(purity): 97.99%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT6.10 min. 0.05% TFA (Aq)+5% ACN: ACN+5% 0.05% TFA (Aq); 1.0 mL/min,Diluent: DMSO:ACN:water).

Synthesis of N-((2-(4-(4-aminobutyl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide hydrochloride salt (11004)

To a stirring solution of 11002 (200 mg, 0.35 mmol) in MeOH (15 mL)under inert atmosphere was added 10% Pd/C (150 mg) at RT and stirredunder hydrogen atmosphere (balloon pressure) at RT for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite and eluted with 20%MeOH/CH₂Cl₂ (250 mL). The filtrate was concentrated in vacuo to obtainthe crude. The crude was purified through basic alumina columnchromatography using NH₄OH: MeOH:CH₂Cl₂ (1:1:8) to afford amine (25 mg,crude)

The above crude amine (25 mg, crude) was dissolved in THF (10 mL) underinert atmosphere was added Et₂O.HCl (5 mL) at 0° C.; warmed to RT andstirred for 2 h. The volatiles were removed in vacuo and the obtainedcrude was triturated with EtOAc (5 mL), diethylether (5 mL) and dried invacuo to afford 11004 (80 mg, 10% over 3 steps) as an off-white solid.TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (400 MHz, DMSO-d₆): δ 11.51(br s, 1H), 9.47 (t, J=5.7 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.01-7.95(m, 2H), 7.90 (td, J=7.5, 1.5 Hz, 1H), 7.87-7.81 (m, 6H), 7.46 (d, J=8.4Hz, 2H), 4.69 (d, J=5.5 Hz, 2H), 2.64-2.49 (m, 4H), 2.22 (s, 6H); LC-MS:95.39%; 547.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.87 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 95.30%; (column; X-select CSH C-18 (150×4.6 mm,3.5 μm); RT 8.39 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min,Diluent: DMSO:ACN).

Synthesis of 11003 & 11005

Synthesis of N-((2-(4-(4-(dimethylamino) but-1-yn-1-yl) phenyl)thiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11003)

To a stirring solution of 11002 (220 mg, 0.40 mmol) in MeOH (15 mL)under inert atmosphere were added paraformaldehyde (60 mg, 2.02 mmol)and sodium cyanoborohydride (127 mg, 2.02 mmol) at RT and stirred for 16h. The reaction was monitored by TLC; after completion of the reaction,the reaction mixture was diluted with water (10 mL) and extracted with10% MeOH/CH₂Cl₂ (2×100 mL). The combined organic extracts were driedover sodium sulfate, filtered and concentrated in vacuo to obtain thecrude. The crude was purified through basic alumina columnchromatography using NH₄OH: MeOH:CH₂Cl₂ (1:1:8) to afford 11003 (140 mg,60%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); 41 NMR(400 MHz, DMSO-d₆): δ 11.50 (s, 1H), 9.47 (t, J=5.6 Hz, 1H), 8.03 (d,J=8.4 Hz, 1H), 7.95 (t, J=7.4 Hz, 2H), 7.91-7.82 (m, 3H), 7.82-7.73 (m,4H), 7.72-7.64 (m, 2H), 7.29 (d, J=7.9 Hz, 2H), 4.65 (d, J=5.3 Hz, 2H),2.81-2.71 (m, 2H), 2.67-2.56 (m, 2H), 1.67-1.44 (m, 4H); LC-MS: 96.66%;571.1 (M⁺+1); (Column; X-select CSH C-18 (150×4.6 mm, 2.7 μm); RT 1.86min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.0 mL/min); HPLC(purity): 98.60%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT6.47 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent:DMSO:ACN).

Synthesis of N-((2-(4-(4-(dimethylamino) butyl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11005)

To a stirring solution of 11003 (140 mg, 0.24 mmol) in MeOH (15 mL)under inert atmosphere was added 10% Pd/C (50 mg) at RT and stirredunder hydrogen atmosphere (balloon pressure) at RT for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was filtered through celite and eluted with 20%MeOH/CH₂Cl₂ (200 mL). The filtrate was concentrated in vacuo to obtainthe crude. The crude was purified through basic alumina columnchromatography using 10% MeOH/CH₂Cl₂ to afford 11005 (15 mg, 10%). TLC:10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (400 MHz, DMSO-d₆): δ 1150 (br s,1H), 9.46 (br t, J=5.5 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.01-7.95 (m,2H), 7.93-7.87 (m, 1H), 7.87-7.76 (m, 6H), 7.29 (d, J=8.1 Hz, 2H), 4.68(br d, J=5.3 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 2.20 (t, J=7.2 Hz, 2H),2.09 (s, 5H), 1.65-1.51 (m, 2H), 1.44-1.36 (m, 2H); LC-MS: 95.02%; 575.1(M⁺+1); (Column; X-select CSH C-18 (150×4.6 mm, 2.7 μm); RT 1.89 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.0 mL/min); HPLC(purity): 97.71%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT9.02 min. 5 mM NH₄OAc: ACN; 1.0 mL/min, Diluent: DMSO:ACN:water).

Synthesis of 11061

Synthesis of N-((2-(4-(4-morpholinobut-1-yn-1-yl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]thiazepine-8-carboxamide 5, 5-dioxide (11061)

To a stirring solution of 4-(4-(5-((5, 5-dioxido-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] thiazepine-8-carboxamido) methyl)thiazol-2-yl) phenyl) but-3-yn-1-yl methanesulfonate 779 (330 mg, crude)in THF (15 mL) was added morpholine 302 (0.23 mL, 2.65 mmol) in a sealedtube at RT under inert atmosphere. The reaction mixture was heated to70° C. and stirred for 16 h. The reaction was monitored by TLC and LCMS;after completion of the reaction, the reaction mixture was diluted withwater (50 mL) and extracted with EtOAc (2×50 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through silica gelcolumn chromatography using 1-5% MeOH/CH₂Cl₂ followed by triturationwith acetonitrile (2×2 mL) to afford 11061 (30 mg, 9%) as an off-whitesolid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (400 MHz, DMSO-d₆): δ11.49 (br s, 1H), 9.48 (t, J=5.6 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H),8.01-7.96 (m, 2H), 7.93-7.79 (m, 7H), 7.46 (d, J=8.4 Hz, 2H), 4.69 (d,J=5.5 Hz, 2H), 3.61-3.55 (m, 4H), 2.64-2.55 (m, 4H), 2.45-2.39 (m, 4H);LC-MS: 93.38%; 613.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 1.87 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 93.71%; (column; X-Select CSH-C-18 (150×4.6 mm,3.5 μm); RT 5.87 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min,Diluent: ACN:H₂O:DMSO).

Synthesis of 1835

Synthesis of N-((2-(4-hydroxybenzyl) thiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] oxazepine-8-carboxamide (1835)

To a stirring solution of N-((2-(4-methoxybenzyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (1835-A) (150 mg, 0.31 mmol) in CH₂Cl₂ (10 mL)under inert atmosphere was added BBr₃ (0.06 mL, 0.63 mmol) at 0° C.;warmed to RT and stirred for 24 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was quenched withice-cold water (10 mL) and the obtained solid was filtered, washed with10% NaHCO₃ solution (100 mL). The obtained solid was dried in vacuo toobtain the crude which was titurated with EtOAc (10 mL) and dried invacuo to afford 1835 (130 mg, 90%) as an off-white solid. TLC: 10%EtOAc/hexanes (R_(f): 0.4); ¹H NMR (DMSO-d₆, 400 MHz): δ 10.59 (s, 1H),9.12-9.06 (m, 1H), 7.78 (dd, J=7.8, 1.6 Hz, 1H), 7.65-7.62 (m, 2H),7.61-7.56 (m, 1H), 7.53 (s, 1H), 7.41-7.31 (m, 3H), 7.08 (d, J=8.5 Hz,2H), 6.69 (d, J=8.4 Hz, 2H), 4.53 (d, J=5.9 Hz, 2H), 4.10 (s, 2H);LC-MS: 94.88%; 458.1 (M+1)⁺; (column; Kinetex EVO C-18 (50×3.0 mm, 2.6um); RT 2.38 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH₄OOCH,0.8 mL/min); HPLC (purity): 97.47%; (column; X-select CSH C-18 (150×4.6mm, 3.5 μm); RT 7.77 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0mL/min, Diluent: DMSO:ACN:water).

Synthesis of 1736

Synthesis of N-((2-(4-hydroxy-3-methylphenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (1736)

To a stirring solution of 1736-A (120 mg, 0.25 mmol) in CH₂Cl₂ (10 mL)was added BBr₃ (0.048 mL, 0.50 mmol) at 0° C.; warmed to RT and stirredfor 16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was quenched with ice-cold water (10 mL).The precipitated solid was filtered, washed with 10% NaHCO₃ solution (20mL), water (10 mL), n-pentane (10 mL) and dried in vacuo to affordcompound 1736 (110 mg, 95%) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂(R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500 MHz): δ 10.64 (s, 1H), 9.84 (s, 1H),9.17 (t, J=5.2 Hz, 1H), 7.78 (d, J=6.9 Hz, 1H), 7.72-7.58 (m, 5H), 7.53(d, J=8.2 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.38-7.31 (m, 2H), 6.83 (d,J=8.3 Hz, 1H), 4.62 (d, J=5.1 Hz, 2H), 2.15 (s, 3H); LC-MS: 95.08%;457.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT2.19 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);HPLC (purity): 97.99%; (column; Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT7.56 min. ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0 mL/min,Diluent: DMSO:ACN:water).

Synthesis of 1738

Synthesis of N-((2-(4-hydroxy-3, 5-dimethylphenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (1738)

To a stirring solution of 1738-A (120 mg, 0.24 mmol) in CH₂Cl₂ (15 mL)was added BBr₃ (62 mg, 0.24 mmol) at 0° C.; warmed to RT and stirred for16 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was cooled to 0° C., quenched withice-cold water (5 mL) and the precipitated solid was filtered washedwith 10% aqueous sodium carbonate solution and in vacuo to obtain thecrude. The crude was titurated with MeOH (2 mL) and dried in vacuo toafford 1738 (100 mg, 86%) as an of-white solid. TLC: 5% MeOH/CH₂Cl₂(R_(f): 0.1); ¹H NMR (DMSO-d₆, 400 MHz): δ 10.64 (s, 1H), 9.18 (t, J=5.8Hz, 1H), 8.74 (br s, 1H), 7.78 (dd, J=7.7, 1.7 Hz, 1H), 7.69 (d, J=2.0Hz, 1H), 7.66-7.60 (m, 3H), 7.45 (s, 2H), 7.42 (d, J=8.4 Hz, 1H),7.38-7.31 (m, 2H), 4.62 (d, J=5.6 Hz, 2H), 2.19 (s, 6H); LC-MS: 96.50%;472.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT2.23 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);HPLC (purity): 98.22%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm);RT 8.70 min. ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0 mL/min,Diluent: DMSO:ACN:water).

Synthesis of 1709

Synthesis of N-((2-(2-hydroxypyrimidin-5-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (1709)

To a stirring solution of N-((2-(2-methoxypyrimidin-5-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, 1] [1, 4]oxazepine-8-carboxamide 1709-A (50 mg, 0.10 mmol) in CH₂Cl₂ (15 mL) wasadded BBr₃ (0.10 mL, 1.08 mmol) at 0° C.; warmed to RT and stirred for24 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was cooled to 0° C., quenched withice-cold water (10 mL) and stirred for 15 min. The obtained solid wasfiltered, washed to with saturated sodium carbonate solution (5 mL) andwater (10 mL) and dried in vacuo to obtain the crude. The crude wastiturated with MeOH (2 mL), diethyl ether (2 mL) and pentane (5 mL) anddried in vacuo to afford 1709 (35 mg, 72%) as an off-white solid. TLC:10% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H NMR (DMSO-d₆, 400 MHz): δ 12.42 (s,1H), 10.65 (s, 1H), 9.22 (t, J=5.7 Hz, 1H), 8.70 (s, 2H), 7.78 (dd,J=7.7, 1.6 Hz, 1H), 7.72-7.68 (m, 2H), 7.66-7.59 (m, 2H), 7.42 (d, J=8.4Hz, 1H), 7.39-7.31 (m, 2H), 4.63 (d, J=5.6 Hz, 2H); LC-MS: 97.71%; 445.9(M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.84 min.0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC(purity): 94.09%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT5.87 min. ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0 mL/min,Diluent: ACN:water).

Synthesis of 1615

Synthesis of methyl (5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamido) methyl) thiazol-2-yl) glycinate (781)

To a stirring solution of compound 149 (150 mg, 0.58 mmol) in DMF (5 mL)under inert atmosphere were added methyl (5-(aminomethyl) thiazol-2-yl)glycinate hydrochloride 623 (139 mg, 0.58 mmol), EDCI.HCl (212 mg, 1.17mmol), HOBt (158 mg, 1.17 mmol) and diisopropylethylamine (0.5 mL, 2.94mmol) at 0° C.; warmed to RT and stirred for 16 h. The reaction wasmonitored by TLC; after completion of the reaction, the reaction mixturewas diluted with water (50 mL) and the precipitated solid was filteredand dried in vacuo to obtain the crude. The crude was purified throughsilicagel column chromatography using 5-10% MeOH/CH₂Cl₂ to affordcompound 781 (72 mg, 27%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(R_(f): 0.4); ¹H-NMR (DMSO-d₆ 500 MHz): δ 10.61 (s, 1H), 8.97 (t, J=5.5Hz, 1H), 7.85-7.76 (m, 1H), 7.70-7.57 (m, 3H), 7.49-7.25 (m, 4H), 6.86(s, 1H), 4.38 (d, J=5.5 Hz, 2H), 3.99 (d, J=6.1 Hz, 2H), 3.62 (s, 3H).

Synthesis of (5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamido) methyl) thiazol-2-yl) glycine (1615)

To a stirring solution of compound 781 (70 mg, 0.16 mmol) in THF:H₂O(1:1, 10 mL) was added lithium hydroxide monohydrate (38.4 mg, 0.80mmol) at RT and stirred for 4 h. The reaction was monitored by TLC;after completion of the reaction, the reaction mixture was diluted withwater (30 mL), washed with EtOAc (2×25 mL). The pH of the aqueous layerwas acidified with 4 N HCl to ˜2. The precipitated solid was filteredand triturated with CH₃CN (2 mL), MeOH:CH₃CN (1:1, 1 mL), MeOH (1 mL)and dried in vacuo to afford 1615 (30 mg, 44%) as an off-white solid.TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 10.60(s, 1H), 8.95 (t, J=5.2 Hz, 1H), 7.77 (dd, J=7.6, 1.4 Hz, 1H), 7.68-7.55(m, 3H), 7.51 (br s, 1H), 7.43-7.28 (m, 3H), 6.85 (s, 1H), 4.36 (d,J=5.6 Hz, 2H), 3.77 (d, J=4.8 Hz, 2H); LC-MS: 93.23%; 424.9 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.86 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity):93.86%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 5.54 min.0.05% TFA (Aq):ACN; 1.0 mL/min).

Synthesis of 1616

Synthesis of methyl 2-((5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1,4]oxazepine-8-carboxamido) methyl) thiazol-2-yl) thio) acetate (782)

To a stirring solution of compound 149 (150 mg, 0.59 mmol) in DMF (5 mL)under inert atmosphere were added EDCI.HCl (224 mg, 1.18 mmol), HOBt(158 mg, 1.18 mmol) and diisopropylethylamine (0.30 mL, 1.81 mmol) andmethyl 2-((5-(aminomethyl) thiazol-2-yl) thio) acetate hydrochloride 627(139 mg, 0.65 mmol) at 0° C.; warmed to RT and stirred for 16 h. Thereaction was monitored by TLC; after completion of the reaction, thereaction mixture was diluted with water (50 mL); the obtained solid wasfiltered, triturated with CH₃CN (2 mL), diethyl ether (5 mL) and driedin vacuo to afford compound 782 (180 mg, 67%) as an off-white solid.TLC: 10% MeOH/CH₂Cl₂ (R_(f). 0.5); ¹H-NMR (DMSO-d₆ 500 MHz): δ 10.60 (s,1H), 9.13 (t, J=5.6 Hz, 1H), 7.76 (d, J=6.7 Hz, 1H), 7.67-7.54 (m, 4H),7.40 (d, J=8.4 Hz, 1H), 7.37-7.29 (m, 2H), 4.52 (d, J=5.5 Hz, 2H), 4.10(s, 2H), 3.62 (s, 3H).

Synthesis of 2-((5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamido) methyl) thiazol-2-yl) thio) acetic acid (1616)

To a stirring solution of compound 782 (150 mg, 0.33 mmol) in THF:H₂O(5:1, 6 mL) was added lithium hydroxide monohydrate (31.6 mg, 0.66 mmol)at RT and stirred for 3 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was diluted with water(50 mL), washed with EtOAc (2×50 mL). The pH of the aqueous layer wasacidified with 4 N HCl to ˜2. The precipitated solid was filtered washedwith CH₃CN (5 mL) and dried in vacuo to afford 1616 (90 mg, 62%) as anoff-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 500MHz): δ 12.98 (br s, 1H), 10.62 (s, 1H), 9.15 (t, J=5.6 Hz, 1H), 7.78(dd, J=7.7, 1.3 Hz, 1H), 7.69-7.58 (m, 3H), 7.56 (s, 1H), 7.42 (d, J=8.4Hz, 1H), 7.38-7.31 (m, 2H), 4.54 (d, J=5.5 Hz, 2H), 4.00 (s, 2H); LC-MS:98.46%; 440.2 (M−1)⁺; (column; X-select C18, (50×3.0 mm, 2.5 μm); RT2.64 min. 5 mM Aq. NH₄OAc+ACN; 0.8 mL/min); HPLC (purity): 96.34%;(column; Zorbax SB C-18 (150×4.6 mm, 3.5μ); RT 7.27 min. ACN: 0.05% TFA(Aq); 1.0 mL/min; Diluent: ACN:water).

Synthesis of 1691

Synthesis of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] oxazepine-8-carboxamide (783)

To a stirring solution of compound 149 (500 mg, 1.96 mmol) in DMF (10mL) under inert atmosphere were added compound 223 (398 mg, 2.15 mmol),EDCI.HCl (561 mg, 2.94 mmol), HOBt (397 mg, 2.94 mmol) anddiisopropylethylamine (1.75 mL, 9.80 mmol) at 0° C.; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with ice cold-water (50mL), extracted with EtOAc (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silicagel columnchromatography using 8% MeOH/to CH₂Cl₂ to afford compound 783 (390 mg,52%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR(DMSO-d₆ 500 MHz): δ 10.63 (s, 1H), 9.23 (t, J=5.6 Hz, 1H), 7.78 (dd,J=7.7, 1.6 Hz, 1H), 7.68 (s, 1H), 7.65-7.58 (m, 3H), 7.43 (d, J=8.4 Hz,1H), 7.39-7.31 (m, 2H), 4.56 (d, J=5.8 Hz, 2H).

Synthesis of N-((2-(3-(dimethylamino) propoxy) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (1691)

To a stirring solution of 3-(dimethylamino) propan-1-ol 364 (0.11 mL,0.97 mmol) in THF (15 mL) under argon atmosphere was added sodiumhydride (60%, 39 mg, 1.62 mmol) at 0° C. and stirred for 15 min. To thiswas added compound 783 (125 mg, 0.32 mmol) at 0° C.; heated to 60° C.and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched with water(5 mL) and the extracted with EtOAc (2×50 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude compound was purified throughsilicagel column chromatography using 5% MeOH/CH₂Cl₂ to afford 1691 (15mg, 10%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4);¹H-NMR (DMSO-d₆, 400 MHz): δ 10.62 (br s, 1H), 9.07 (t, J=5.3 Hz, 1H),7.78 (dd, J=7.8, 1.6 Hz, 1H), 7.68-7.56 (m, 3H), 7.41 (d, J=8.4 Hz, 1H),7.38-7.31 (m, 2H), 7.05 (s, 1H), 4.44 (d, J=5.6 Hz, 2H), 4.32 (t, J=6.5Hz, 2H), 2.28 (t, J=7.0 Hz, 2H), 2.11 (s, 6H), 1.88-1.79 (m, 2H); LC-MS:95.08%; 453.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.73 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 93.73%; (column; Zorbax SB C-18 (150×4.6 mm, 3.5μm); RT 5.64 min. ACN: 0.05% TFA (Aq); 1.0 mL/min).

Synthesis of 1687

Synthesis of N-((2-(3-(dimethylamino) propoxy) thiazol-5-yl)methyl)-N-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (1687)

To a stirring solution of 3-(dimethylamino) propan-1-ol 364 (0.14 mL,1.12 mmol) in THF (10 mL) under argon atmosphere was added sodiumhydride (60%, 41 mg, 1.69 mmol) portion wise at 0° C. and stirred for 10min. To this was added compound 784 (150 mg, 0.37 mmol) at 0° C.; heatedto 60° C. and stirred for 4 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched with water(0.5 mL) and the volatiles were removed in vacuo to obtain the crude.The crude compound was purified through basic alumina columnchromatography using 2% MeOH/CH₂Cl₂ to afford 1687 (75 mg, 43%) as anoff-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400MHz): δ 10.56 (br s, 1H), 7.79 (dd, J=7.8, 1.6 Hz, 1H), 7.64-7.60 (m,1H), 7.42-7.31 (m, 3H), 7.23-7.17 (m, 3H), 4.59 (br s, 2H), 4.35 (t,J=6.5 Hz, 2H), 2.85 (s, 3H), 2.30 (t, J=7.1 Hz, 2H), 2.12 (s, 6H),1.88-1.81 (m, 2H); LC-MS: 97.53%; 467.1 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 1.75 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.51%; (column;X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 5.80 min. 0.05% TFA (Aq):ACN; 1.0 mL/min).

Synthesis of 1614

Synthesis of N-((2-(2-(dimethylamino) ethoxy) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (1614)

To a stirring solution of 2-(dimethylamino) ethan-1-ol 358 (70 mg, 0.77mmol) in THF (10 mL) under argon atmosphere was added sodium hydride(60%, 28 mg, 1.16 mmol) at 0° C. and stirred for 10 min. To this wasadded N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b,f] [1, 4] oxazepine-8-carboxamide 783 (150 mg, 0.38 mmol) at 0° C.;heated to reflux and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was quenchedwith ice-cold water (5 mL) and the extracted with EtOAc (2×50 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude compound waspurified through silicagel column chromatography using 10% MeOH/CH₂Cl₂and further purified by preparative HPLC purification to afford 1614 (35mg, 20%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4);¹H-NMR (DMSO-d₆, 500 MHz): δ 10.64 (s, 1H), 9.12 (t, J=5.6 Hz, 1H), 7.78(dd, J=7.7. 1.6 Hz, 1H), 7.69 (s, 1H), 7.65-7.58 (m, 2H), 7.41 (d, J=8.4Hz, 1H), 7.38-7.31 (m, 2H), 7.05 (s, 1H), 4.44 (d, J=5.5 Hz, 2H), 4.37(t, J=5.6 Hz, 2H), 2.59 (t, J=5.5 Hz, 2H), 2.16 (s, 6H); LC-MS: 99.24%;439.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT1.95 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);HPLC (purity): 98.60%; (column; Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT5.65 min. 0.05% TFA (Aq): ACN; 1.0 mL/min).

Synthesis of 1686

Synthesis of N-((2-chlorothiazol-5-yl) methyl)-N-methyl-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] oxazepine-8-carboxamide (784)

To a stirring solution of compound 149 (400 mg, 1.57 mmol) in DMF (5 mL)under argon atmosphere were added EDCI.HCl (570 mg, 3.15 mmol), HOBt(425 mg, 3.15 mmol) at 0° C. RT and stirred for 10 min. To this wereadded compound 368 (280 mg, 1.73 mmol) and diisopropylethylamine (0.8mL, 4.72 mmol) at RT and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the reaction mixture was dilutedwith ice-cold water (50 mL) and the obtained solid was filtered,triturated with CH₃CN: diethyl ether (1:4, 10 mL) and dried in vacuo toafford compound 784 (520 mg, 89%) as an off-white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H-NMR (DMSO-d₆, 500 MHz): δ 10.56 (br s, 1H),7.79 (dd, J=7.7, 1.0 Hz, 1H), 7.71 (br s, 1H), 7.66-7.61 (m, 1H),7.42-7.31 (m, 3H), 7.27-7.20 (m, 2H), 4.70 (br s, 2H), 2.89 (s, 3H).

Synthesis of N-((2-(2-(dimethylamino) ethoxy) thiazol-5-yl)methyl)-N-methyl-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (1686)

To a stirring solution of 2-(dimethylamino) ethan-1-ol 358 (0.12 mL,1.12 mmol) in THF (10 mL) under argon atmosphere was added sodiumhydride (60%, 41 mg, 1.69 mmol) portion wise at 0° C. and stirred for 10min. To this was added compound 784 (150 mg, 0.37 mmol) at 0° C.; heatedto 60° C. and stirred for 4 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched with water(0.5 mL) and the volatiles were removed in vacuo to obtain the crude.The crude compound was purified through basic alumina columnchromatography using 2% MeOH/CH₂Cl₂ to afford 1686 (85 mg, 50%) as anoff-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 500MHz): δ 10.56 (br s, 1H), 7.79 (dd, J=7.8, 1.6 Hz, 1H), 7.66-7.60 (m,1H), 7.42-7.31 (m, 3H), 7.24-7.16 (m, 3H), 4.59 (br s, 2H), 4.40 (t,J=5.6 Hz, 2H), 2.85 (s, 3H), 2.62 (t, J=5.6 Hz, 2H), 2.19 (s, 6H);LC-MS: 98.25%; 453.1 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm,2.7 μm); RT 1.72 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 97.15%; (column; X-select CSH C-18 (150×4.6 mm,3.5 μm); RT 5.67 min. 0.05% TFA (Aq): ACN; 1.0 mL/min).

Synthesis of 1613-A

Synthesis of 2-((tetrahydro-2H-pyran-2-yl) oxy) ethan-1-ol (787)

To a stirring solution of ethane-1, 2-diol 785 (20 g, 322.5 mmol) inCH₂Cl₂ (250 mL) under inert atmosphere was added p-toluene sulfonic acid(3 g, 0.16 mmol) and 3, 4-dihydro-2H-pyran 786 (13.5 g, 0.16 mmol) at 0°C.; warmed to RT and stirred for 16 h. The reaction was monitored byTLC; after completion of the reaction, the diluted with CH₂Cl₂ (200 mL)and washed with water (100 mL). The organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using30% EtOAc/hexanes to afford compound 787 (6 g, 13%) as colorless thicksyrup. TLC: 50% EtOAc/hexanes (R_(f): 0.4); ¹H-NMR (CDCl₃, 400 MHz): δ4.74-4.53 (m, 1H), 3.98-3.61 (m, 5H), 3.59-3.48 (m, 1H), 1.91-1.68 (m,2H), 1.66-1.48 (m, 5H).

Synthesis of 11-oxo-N-((2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (1613-A)

To a stirring solution of compound 787 (19 mg, 0.12 mmol) in THF (4 mL)under argon atmosphere was added sodium hydride (60%, 4.5 mg, 0.18 mmol)at 0° C. and stirred for 30 min. To this was addedN-((2-chlorothiazol-5-yl) methyl)-11-oxo-10, 11-dihydrodibenzo [b, f][1, 4] oxazepine-8-carboxamide 783 (25 mg, 0.06 mmol) at 0° C.; heatedto 60° C. and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the reaction mixture was quenched withsaturated citric acid solution (1 mL) and the extracted with EtOAc (2×25mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo. The crude compound was diluted with10% MeOH/CH₂Cl₂ (20 mL), saturated citric acid solution (3 mL) and theorganic extract was dried over sodium sulfate, filtered and concentratedin vacuo to obtain the crude; which was triturated CH₃OH (2×2 mL) anddried in vacuo to afford 1613-A (12 mg, 45%) as an off-white solid. TLC:5% MeOH/CH₂Cl₂ (R_(f). 0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 10.62 (s, 1H),9.09 (t, J=5.7 Hz, 1H), 7.78 (dd, J=7.7, 1.7 Hz, 1H), 7.68-7.57 (m, 3H),7.41 (d, J=8.5 Hz, 1H), 7.38-7.31 (m, 2H), 7.05 (s, 1H), 4.91 (t, J=5.5Hz, 1H), 4.44 (d, J=5.5 Hz, 2H), 4.30 (t, J=5.2 Hz, 2H), 3.68 (q, J=5.2Hz, 2H); LC-MS: 96.28%; 412.0 (M⁺+1); (column; X-Select CSH C-18,(50×3.0 mm, 2.5 μm); RT 2.46 min. 2.5 mM Aq. NH₄OOCH+5% ACN: ACN+5% 2.5mM Aq. NH₄OOCH, 1.2 mL/min); HPLC (purity): 96.02%; (column; X-selectCSH C-18 (150×4.6 mm, 3.5 μm); RT 8.39 min. 0.05% TFA (Aq): ACN; 1.0mL/min).

Synthesis of 1705 and 1706

Synthesis of N-((2-(6-methoxypyridin-3-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (1705)

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] oxazepine-8-carboxamide 783 (300 mg,0.77 mmol) in 1, 2 dimethoxy ethane: H₂O (4:1, 10 mL) were added(6-methoxypyridin-3-yl) boronic acid 582 (143 mg, 0.93 mmol), sodiumcarbonate (244 mg, 2.31 mmol) in a sealed tube and purged under argonatmosphere for 15 min. To this was added Pd(PPh₃)₄ (88 mg, 0.07 mmol) atRT; heated to 110° C. and stirred for 16 h. The reaction was monitoredby TLC; after completion the reaction mixture was diluted with water (50mL) and extracted with CH₂Cl₂ (2×30 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 2-8% MeOH/CH₂Cl₂ to afford 1705 (160 mg, 45%) as anoff-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 500MHz): δ 10.65 (s, 1H), 9.23 (t, J=5.8 Hz, 1H), 8.68 (d, J=2.0 Hz, 1H),8.16 (dd, J=8.7, 2.5 Hz, 1H), 7.80-7.76 (m, 2H), 7.70 (d, J=2.0 Hz, 1H),7.66-7.60 (m, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.39-7.29 (m, 2H), 6.92 (d,J=8.7 Hz, 1H), 4.66 (d, J=5.6 Hz, 2H), 3.90 (s, 3H); LC-MS: 98.15%;459.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT2.26 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC(purity): 99.44%; (column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT8.52 min. ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0 mL/min,Diluent: ACN:water).

Synthesis of N-((2-(6-hydroxypyridin-3-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (1706)

To a stirring solution of 1705 (100 mg, 0.21 mmol) in DMF (5 mL) underinert atmosphere were added lithium chloride (46 mg, 1.08 mmol)p-toluenesulfonic acid (215 mg, 1.08 mmol) at RT in a sealed tube;heated to 120° C. and stirred for 16 h. The reaction was monitored byTLC and LC-MS; after completion the reaction mixture was diluted withwater (50 mL) and the precipitate was filtered. The solid was suspendedin EtOAc (10 mL), stirred for 5 h, filtered and dried in vacuo to afford1706 (40 mg, 42%) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f):0.4); ¹H-NMR (DMSO-d₆, 500 MHz): δ 11.72 (br s, 1H), 10.62 (br s, 1H),9.18 (t, J=5.2 Hz, 1H), 7.92 (br s, 1H), 7.88 (d, J=9.5 Hz, 1H), 7.77(d, J=7.5 Hz, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.64-7.59 (m, 2H), 7.41 (d,J=8.4 Hz, 1H), 7.37-7.30 (m, 2H), 6.41 (d, J=9.5 Hz, 1H), 4.60 (d, J=5.2Hz, 2H); LC-MS: 94.14%; 445.0 (M⁺+1); (column; Ascentis Express C18,(50×3.0 mm, 2.7 μm); RT 1.90 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025%Aq. TFA, 1.2 mL/min); HPLC (purity): 93.67%; (column; X-select CSH C-18(150×4.6 mm, 3.5 μm); RT 6.06 min. ACN+5% 0.05% TFA (Aq): 0.05% TFA(Aq)+5% ACN; 1.0 mL/min, Diluent: DMSO:ACN:water).

Synthesis of 1707

Synthesis of 2-nitro-5-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) pyridine (789)

To a stirring solution of 5-bromo-2-nitropyridine 788 (1 g, 4.95 mmol)in 1, 4-dioxane (20 mL) under inert atmosphere were added bispinacolatodiboron (1.9 g, 7.42 mmol), potassium acetate (1.45 g, 14.85 mmol) at RTand purged under argon atmosphere for 15 min; to this was addedPd(dppf)Cl₂ (362 mg, 0.49 mmol) and purged under argon atmosphere for 5min, heated to 100° C. and stirred for 4 h. The reaction was monitoredby TLC; after completion of the reaction, the volatiles wereconcentrated in vacuo to obtain the crude. The crude was triturated withdiethylether (20 mL) and dried in vacuo to afford compound 789 (980 mg,crude) as an brown sticky solid. TLC: 20% MeOH/CH₂Cl₂ (R_(f): 0.2);

Synthesis of N-((2-(6-nitropyridin-3-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (790)

To a stirring solution N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] oxazepine-8-carboxamide 783 (300 mg,0.77 mmol) in 1, 2-dimethoxy ethane: H₂O (4:1, 20 mL) under inertatmosphere were added 2-nitro-5-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) pyridine 789 (600 mg, crude) and sodium carbonate(248 mg, 2.33 mmol) at RT and purged under argon atmosphere for 15 min.To this was added Pd(dppf)Cl₂ (57 mg, 0.07 mmol) and heated to 100° C.and stirred for 16 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 4% MeOH/CH₂Cl₂ to afford compound 790 (200 mg, 54%)as an off-white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.3). LC-MS: 47.25%;474.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT2.249 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2 mL/min).

Synthesis of N-((2-(6-aminopyridin-3-yl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (1707)

To a stirring solution of compound 790 (100 mg, 0.21 mmol) in EtOH: H₂O(1:1, 10 mL) under inert atmosphere were added iron powder (118 mg, 2.11mmol), ammonium chloride (113 mg, 2.11 mmol) at RT; heated to 90° C. for2 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was filtered through celite and washedwith 5% MeOH/CH₂Cl₂ (30 mL). The filtrate was concentrated in vacuo toobtain the crude. The crude was purified through silicagel columnchromatography using 5% MeOH/CH₂Cl₂, triturated with EtOAc (10 mL), MeOH(10 mL) and dried in vacuo to afford 1707 (20 mg, 21%) as an off-whitesolid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (DMSO-d₆, 400 MHz): δ10.63 (s, 1H), 9.17 (t, J=5.8 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 7.85-7.76(m, 2H), 7.71-7.59 (m, 4H), 7.42 (d, J=8.3 Hz, 1H), 7.39-7.30 (m, 2H),6.53-6.47 (m, 3H), 4.61 (d, J=5.5 Hz, 2H); LC-MS: 98.86%; 444.0 (M⁺+1);(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.76 min. 0.025%Aq.TFA+5% ACN: ACN+5% 0.025% Aq TFA, 1.2 mL/min). HPLC (purity): 96.35%;(column; X-select CSH C-18 (150×4.6 mm, 3.5 μm); RT 5.61 min. 5% ACN+5%0.05% TFA (Aq): ACN+5% 0.05% TFA; 1.0 mL/min, Diluent: ACN:water).

Synthesis of 1770, 1770-A

Synthesis of N-((2-(4-cyanophenyl) thiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] oxazepine-8-carboxamide (1770-A)

To a stirring solution of 149 (150 mg, 0.58 mmol) in DMF (7.5 mL) underinert atmosphere were added EDCI.HCl (168 mg, 0.88 mmol), HOBt (119 mg,0.88 mmol), 4-(5-(aminomethyl) thiazol-2-yl) benzonitrile hydrochloride227 (148 mg, 0.58 mmol) and diisopropylethylamine (0.32 mL, 1.76 mmol)at 0° C.; warmed to RT and stirred for 16 h. The reaction was monitoredby TLC; after completion of the reaction, the reaction mixture wasdiluted with water (50 mL) and extracted with 10% MeOH/CH₂Cl₂ (2×100mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through silicagel column chromatography using 5% MeOH/CH₂Cl₂ toafford 1770-A (120 mg, 45%) as white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f):0.5); ¹H NMR (DMSO-d₆, 400 MHz): δ 10.65 (s, 1H), 9.27 (t, J=5.6 Hz,1H), 8.07 (d, J=8.5 Hz, 2H), 7.97-7.88 (m, 3H), 7.78 (dd, J=7.7, 1.6 Hz,1H), 7.70 (s, 1H), 7.66-7.60 (m, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.39-7.31(m, 2H), 4.69 (d, J=5.6 Hz, 2H); LC-MS: 99.16%; 453.2 (M⁺+1); (column;Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 2.35 min. 0.025% Aq.TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 98.94%;(column; X-Select CSH C-18 (150×4.6 mm, 3.5 μm); RT 8.92 min. ACN+5%0.05% TFA (Aq): 0.05% TFA (Aq): 5% ACN; 1.0 mL/min, Diluent: ACN:water).

Synthesis of N-((2-(4-carbamoylphenyl) thiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, f] [1, 4] oxazepine-8-carboxamide (1770)

To a stirring solution of 1770-A (80 mg, 0.17 mmol) in DMSO (3 mL) underinert atmosphere were added potassium carbonate (122 mg, 0.88 mmol), 30%hydrogen peroxide (0.16 mL, 1.41 mmol) at 0° C.; warmed to RT andstirred for 2 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with ice-cold water andthe precipitated solid was filtered, washed with MeOH: EtOAc (1:1, 20mL). The obtained solid was suspended in 50% n-pentane/diethylether (10mL) and stirred for 16 h, the solvent was decanted and the solid wasdried in vacuo to afford 1770 (25 mg, 30%) as white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.3); ¹H NMR (DMSO-d₆, 500 MHz): δ 10.62 (br s, 1H),9.29 (br s, 1H), 8.06 (br s, 1H), 7.96-7.94 (m, 4H), 7.84 (s, 1H), 7.74(dd, J=7.7, 1.5 Hz, 1H), 7.69 (s, 1H), 7.62-7.54 (m, 2H), 7.44 (br s,1H), 7.37 (d, J=8.3 Hz, 1H), 7.34-7.27 (m, 2H), 4.67 (s, 2H); LC-MS:99.24%; 471.0 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7μm); RT 1.96 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2mL/min); HPLC (purity): 99.45%; (column; X-select CSH C-18 (150×4.6 mm,3.5 μm); RT 6.96 min. ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0mL/min, Diluent: DMSO:ACN:water).

Synthesis of 1612-A & 1612

Synthesis of methyl 4-(5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamido) methyl) thiazol-2-yl) benzoate (1612-A)

To a stirring solution of compound 149 (150 mg, 0.58 mmol) in DMF (6 mL)under inert atmosphere were added EDCI.HCl (167 mg, 0.88 mmol), HOBt(119 mg, 0.88 mmol), methyl 4-(5-(aminomethyl) thiazol-2-yl) benzoatehydrochloride 636 (183 mg, 0.64 mmol) and diisopropylethylamine (0.50mL, 2.94 mmol) at 0° C.; warmed to RT and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction, the reactionmixture was poured into ice-cold water (50 mL) and stirred for 10 min.The precipitated solid was filtered and dried in vacuo to obtain thecrude. The crude was purified through silica gel column chromatographyusing 2% MeOH/CH₂Cl₂ to afford compound 1612-A (160 mg, 56%) as anoff-white solid. TLC: 10% MeOH/CH₂Cl₂ (R₁. 0.5); ¹H NMR (DMSO-d₆, 500MHz): δ 10.64 (s, 1H), 9.25 (t, J=5.6 Hz, 1H), 8.04 (s, 4H), 7.88 (s,1H), 7.78 (dd, J=7.8, 1.4 Hz, 1H), 7.70 (s, 1H), 7.66-7.61 (m, 2H), 7.43(d, J=8.4 Hz, 1H), 7.39-7.31 (m, 2H), 4.69 (d, J=5.8 Hz, 2H), 3.87 (s,3H); LC-MS: 97.06%; 485.9 (M⁺+1); (column; Ascentis Express C18, (50×3.0mm, 2.7 μm); RT 2.45 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA,1.2 mL/min); HPLC (purity): 97.26%; (column; X-select CSH C-18 (150×4.6mm, 3.5 μm); RT 9.55 min. ACN+0.5% TFA (Aq): 0.5% TFA (Aq)+ACN; 1.0mL/min, Diluent: ACN:water).

Synthesis of 4-(5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamido) methyl) thiazol-2-yl) benzoic acid (1612)

To a stirring solution of 1612-A (60 mg, 0.12 mmol) in THF:H₂O (4:1, 5mL) was added lithium hydroxide monohydrate (11 mg, 0.24 mmol) at RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was diluted with ice-cold water (10mL) and the pH was adjusted to with 2 N HCl to ˜4. The precipitatedsolid was filtered washed with water (20 mL) diethyl ether (5 mL),n-pentane (10 mL) and dried in vacuo to afford 1612 (50 mg, 86%) as anoff-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (DMSO-d₆, 400MHz): δ 13.12 (br s, 1H), 10.64 (s, 1H), 9.26 (t, J=5.7 Hz, 1H),8.02-7.99 (m, 4H), 7.87 (s, 1H), 7.78 (dd, J=7.7, 1.7 Hz, 1H), 7.70 (s,1H), 7.66-7.60 (m, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.39-7.31 (m, 2H), 4.68(d, J=5.5 Hz, 2H); LC-MS: 96.31%; 472.0 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.21 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.41%; (column;Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT 6.86 min. ACN+5% 0.5% TFA (Aq):0.5% TFA (Aq)+5% ACN; 1.0 mL/min, Diluent: ACN:water).

Synthesis of 1620

Synthesis of ethyl 2-(4-(5-((11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamido)methyl)thiazol-2-yl)phenoxy)acetate(791)

To a stirring solution of compound 149 (75 mg, 0.29 mmol) in DMF (5 mL)under inert atmosphere were added ethyl 2-(4-(5-(aminomethyl)thiazol-2-yl) phenoxy) acetate hydrochloride 639 (96 mg, 0.29 mmol),EDCI.HCl (84 mg, 0.44 mmol), HOBt (60 mg, 0.44 mmol), anddiisopropylethylamine (0.27 mL, 1.47 mmol) at 0° C.; warmed to RT andstirred for 16 h. The reaction was monitored by TLC; after completion ofthe reaction, the reaction mixture was poured into ice-cold water (50mL) and extracted with EtOAc (2×150 mL). The combined organic extractswere dried over sodium sulfate, filtered and concentrated in vacuo toobtain the crude. The crude was purified through silica gel columnchromatography using 3% MeOH/CH₂Cl₂ to afford compound 791 (60 mg, 39%)as white solid. TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.6); ¹H NMR (DMSO-d₆, 500MHz): δ 10.63 (s, 1H), 9.19 (t, J=5.8 Hz, 1H), 7.81 (d, J=9.0 Hz, 2H),7.78 (dd, J=7.8, 1.4 Hz, 1H), 7.73-7.69 (m, 2H), 7.65-7.61 (m, 2H), 7.42(d, J=8.4 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.35-7.31 (m, 1H), 7.01 (d,J=9.0 Hz, 2H), 4.84 (s, 2H), 4.64 (d, J=5.5 Hz, 2H), 4.17 (q, J=7.2 Hz,2H), 1.21 (t, J=7.1 Hz, 3H).

Synthesis of 2-(4-(5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) acetic acid(1620)

To a stirring solution of compound 791 (60 mg, 0.11 mmol) in THF:H₂O(4:1, 6 mL) was added lithium hydroxide monohydrate (24 mg, 0.56 mmol)at RT and stirred for 2 h. The reaction was monitored by TLC; aftercompletion of the reaction, the volatiles were removed in vacuo. Theresidue was diluted water (50 mL) and the pH was acidified with 2 N HClto ˜6. The precipitated solid was filtered and dried in vacuo to afford1620 (50 mg, 88%) as white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.2);¹H-NMR (DMSO-d₆, 500 MHz): δ 13.05 (br s, 1H), 10.63 (s, 1H), 9.20 (t,J=5.8 Hz, 1H), 7.81 (d, J=9.0 Hz, 2H), 7.78 (dd, J=7.8, 1.7 Hz, 1H),7.72-7.69 (m, 2H), 7.65-7.61 (m, 2H), 7.42 (d, J=8.4 Hz, 1H), 7.36 (d,J=8.1 Hz, 1H), 7.35-7.31 (m, 1H), 7.00 (d, J=9.0 Hz, 2H), 4.74 (s, 2H),4.64 (d, J=5.5 Hz, 2H); LC-MS: 98.03%; 501.9 (M⁺+1); (column; AscentisExpress C18, (50×3.0 mm, 2.7 μm); RT 2.11 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 99.39%; (column;Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT 7.71 min; ACN+0.5% TFA (Aq):0.5% TFA (Aq): 5% ACN; 1.0 mL/min, Diluent: ACN:water).

Synthesis of 11161

Synthesis of N-((2-(4-(3-hydroxypropoxy) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (792)

To a stirring solution of 11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxylic acid 149 (1 g, 3.94 mmol) in DMF (30 mL) wereadded 3-(4-(5-(aminomethyl) thiazol-2-yl) phenoxy) propan-1-olhydrochloride 734 (1.3 g, 4.33 mmol), EDCI.HCl (1.13 g, 5.9 mmol), HOBt(797 mg, 5.9 mmol) followed by diisopropylethylamine (3.43 mL, 19.68mmol) at 0° C. under inert atmosphere. The reaction mixture wasgradually warmed to RT and stirred for 16 h. The reaction was monitoredby TLC and LCMS; after completion of the reaction, the reaction mixturewas diluted with ice cold water (100 mL) and extracted with EtOAc (2×100mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to obtain the crude. The crude waspurified through column chromatography using 1-5% MeOH/CH₂Cl₂ followedby triturations with 5% MeOH/CH₂Cl₂ (2×5 mL) to afford compound 792 (800mg, 41%) as an off white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.5); ¹HNMR (400 MHz, DMSO-d₆): δ 10.64 (s, 1H), 9.20 (t, J=5.8 Hz, 1H),7.83-7.76 (m, 3H), 7.72-7.68 (m, 2H), 7.66-7.60 (m, 2H), 7.43 (d, J=8.4Hz, 1H), 7.38-7.31 (m, 2H), 7.01 (d, J=8.9 Hz, 2H), 4.63 (d, J=5.6 Hz,2H), 4.56 (t, J=5.1 Hz, 1H), 4.08 (t, J=6.3 Hz, 2H), 3.55 (q, J=6.0 Hz,2H), 1.91-1.82 (m, 2H); LC-MS: 95.30%; 502.2 (M⁺+1); (column; KinetexEVO C-18 (50×3.0 mm, 2.6 um); RT 2.49 min. 2.5 mM NH₄OOCH in water+5%ACN: ACN+5% 2.5 mM NH₄OOCH in water, 0.8 mL/min).

Synthesis of 3-(4-(5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) propylmethanesulfonate (793)

To a stirring solution of compound 792 (200 mg, 0.4 mmol) in CH₂Cl₂ (10mL) were added triethylamine (0.33 mL, 2.39 mmol) followed bymethanesulfonyl chloride (0.1 mL, 1.2 mmol) at 0° C. under inertatmosphere. The reaction mixture was gradually warmed to RT and stirredfor 4 h. The reaction was monitored by TLC; after completion of thereaction, the reaction mixture was quenched with saturated sodiumbicarbonate solution (50 mL) and extracted with CH₂Cl₂ (2×50 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to afford compound 793 (250 mg) as pale brownviscous syrup. This crude material was taken to next step withoutfurther purification. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.6); LC-MS: 46.00%;580.1 (M⁺+1); (column; Kinetex EVO C-18 (50×3.0 mm, 2.6 um); RT 2.85min. 2.5 mM NH₄OOCH in water+5% ACN: ACN+5% 2.5 mM NH₄OOCH in water, 0.8mL/min).

Synthesis of N-((2-(4-(3-morpholinopropoxy) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (11161)

To a stirring solution of compound 793 (180 mg, crude) in THF (5 mL) wasadded morpholine (0.11 mL, 1.29 mmol) in a sealed tube at RT under inertatmosphere. The reaction mixture was heated to 70° C. and stirred for 16h. The reaction was monitored by TLC and LCMS; after completion of thereaction, the reaction mixture was diluted with water (100 mL) andextracted with EtOAc (2×100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to obtainthe crude. The crude was purified through silica gel columnchromatography using 2-10% MeOH/CH₂Cl₂ followed by trituration with 10%MeOH/CH₂Cl₂ (2×2 mL) to afford 11161 (80 mg, 32%) as an off-white solid.TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H NMR (400 MHz, DMSO-d₆): δ 10.64(s, 1H), 9.19 (t, J=5.8 Hz, 1H), 7.82-7.76 (m, 3H), 7.72-7.69 (m, 2H),7.66-7.61 (m, 2H), 7.42 (d, J=8.4 Hz, 1H), 7.39-7.31 (m, 2H), 7.01 (d,J=8.9 Hz, 2H), 4.63 (d, J=5.6 Hz, 2H), 4.06 (t, J=6.4 Hz, 2H), 3.56 (t,J=4.6 Hz, 4H), 2.44-2.33 (m, 6H), 1.91-1.85 (m, 2H); LC-MS: 92.40%;571.2 (M⁺+1); (column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT1.85 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);HPLC (purity): 94.04%; (column; X-Select CSH-C-18 (150×4.6 mm, 3.5 μm);RT 5.75 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent:ACN:H₂O:DMSO).

Synthesis of 11160

Synthesis of 11-oxo-N-((2-(4-(3-(piperidin-1-yl) propoxy) phenyl)thiazol-5-yl) methyl)-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide (11160)

To a stirring solution of 3-(4-(5-((11-oxo-10, 11-dihydrodibenzo [b, 1][1, 4] oxazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) propylmethanesulfonate 793 (250 mg, 0.43 mmol) in THF (5 mL) was addedpiperidine 472 (0.21 mL, 2.15 mmol) at RT under inert atmosphere. Thereaction mixture was heated to 70° C. and stirred for 16 h. The reactionwas monitored by TLC; after completion of the reaction mixture wasdiluted with water (50 mL), and extracted with EtOAc (2×50 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to obtain the crude. The crude was purifiedthrough silica gel column chromatography using 1-6% MeOH/CH₂Cl₂ whichwas further triturated with 10% MeOH/CH₂Cl₂ (2×5 mL) to afford 11160 (90mg, 36%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.3); ¹HNMR (400 MHz, DMSO-d₆): δ 10.65 (s, 1H), 9.22 (t, J=5.7 Hz, 1H),7.85-7.74 (m, 3H), 7.71-7.68 (m, 2H), 7.66-7.60 (m, 2H), 7.42 (d, J=8.4Hz, 1H), 7.38-7.28 (m, 2H), 7.02 (d, J=8.9 Hz, 2H), 4.63 (d, J=5.5 Hz,2H), 4.08 (t, J=6.1 Hz, 2H), 2.92-2.62 (m, 4H), 2.46-2.35 (m, 2H),2.03-2.01 (m, 2H), 1.61-1.63 (m, 4H), 1.46-1.44 (m, 2H); LC-MS: 99.16%;569.3 (M⁺+1); (column; Ascentis Express C-18, (50×3.0 mm, 2.7 μm); RT1.87 min. 0.025% Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min);HPLC (purity): 99.01%; (column; X-Select CSH-C-18 (150×4.6 mm, 3.5 μm);RT 6.03 min. 0.05% TFA+5% ACN: ACN+5% 0.05% TFA; 1.0 mL/min, Diluent:DMSO:ACN).

Synthesis of 11162

Synthesis of N-((2-(4-(3-(diethylamino) propoxy) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide hydrochloride (11162)

To a stirring solution of 3-(4-(5-((11-oxo-10, 11-dihydrodibenzo [b, f][1, 4] oxazepine-8-carboxamido) methyl) thiazol-2-yl) phenoxy) propylmethanesulfonate 793 (200 mg, 0.34 mmol) in THF (10 mL) was addeddiethylamine hydrochloride 387 (1 mL, 1.04 mmol) at RT under inertatmosphere. The reaction mixture was heated to 80° C. and stirred for 16h in a sealed tube. The reaction was monitored by TLC; after completionof the reaction, the volatiles were removed in vacuo to obtain thecrude. The crude was purified through silica gel column chromatographyusing 5% MeOH/CH₂Cl₂ to afford 11162 (80 mg, 41%) as an off white solid.TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H NMR (400 MHz, DMSO-d₆): δ 10.65 (s,1H), 9.86 (br s, 1H), 9.23 (t, J=5.8 Hz, 1H), 7.82 (d, J=8.8 Hz, 2H),7.78 (dd, J=7.7, 1.6 Hz, 1H), 7.71-7.69 (m, 2H), 7.64-7.61 (m, 2H), 7.43(d, J=8.4 Hz, 1H), 7.38-7.29 (m, 2H), 7.03 (d, J=8.9 Hz, 2H), 4.63 (d,J=5.6 Hz, 2H), 4.12 (t, J=6.0 Hz, 2H), 3.20-3.11 (m, 6H), 2.12 (br s,2H), 1.21 (br s, 6H); LC-MS: 95.66%; 557.1 (M⁺+1); (column; AscentisExpress C-18, (50×3.0 mm, 2.7 μm); RT 1.97 min. 0.025% Aq. TFA+5% ACN:ACN+5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.95%; (column;X-Select CSH-C-18 (150×4.6 mm, 3.5 μm); RT 5.94 min. 0.05% TFA+5% ACN:ACN+5% 0.05% TFA; 1.0 mL/min, Diluent: H₂O: ACN).

Synthesis of 1712

Synthesis of tert-butyl (4-(5-((11-oxo-10, 11-dihydrodibenzo [b, f] [1,4] oxazepine-8-carboxamido) methyl) thiazol-2-yl) benzyl) carbamate(795)

To a stirring solution of N-((2-chlorothiazol-5-yl) methyl)-11-oxo-10,11-dihydrodibenzo [b, 1] [1, 4] oxazepine-8-carboxamide 783 (150 mg,0.38 mmol) in 1, 2 dimethoxy ethane: H₂O (4:1, 6 mL) were addedtert-butyl (4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl)carbamate 794 (259 mg, 0.77 mmol), sodium carbonate (144 mg, 1.36 mmol)and purged under argon atmosphere for 15 min. To this was addedPd(PPh₃)₄ (45 mg, 0.039 mmol) at RT; heated to 100° C. and stirred for16 h. The reaction was monitored by TLC; after completion the reactionmixture was diluted with water (100 mL) and extracted with 10%MeOH/CH₂Cl₂ (2×100 mL). The combined organic extracts were dried oversodium sulfate, filtered and concentrated in vacuo to obtain the crude.The crude was purified through silica gel column chromatography using 4%MeOH/CH₂Cl₂ to afford compound 795 (150 mg, 69%) as white solid. TLC: 5%MeOH/CH₂Cl₂ (R_(f): 0.4); ¹H-NMR (DMSO-d₆, 400 MHz): δ 10.77 (s, 1H),9.35 (t, J=5.6 Hz, 1H), 7.97 (d, J=8.1 Hz, 2H), 7.94-7.89 (m, 2H), 7.84(s, 1H), 7.80-7.74 (m, 2H), 7.59-7.54 (m, 2H), 7.52-7.43 (m, 4H), 4.79(d, J=5.5 Hz, 2H), 4.29 (d, J=5.8 Hz, 2H), 1.53 (s, 9H); LC-MS: 94.24%;557.1 (M⁺+1); (column; X Select CSH C-18, (50×3.0 mm, 2.5 μm); RT 3.19min. 2.5 mM Aq. NH4OOCH+5% ACN: ACN+5% 2.5 mM Aq.NH4OOCH, 0.8 mL/min).

Synthesis of N-((2-(4-(aminomethyl) phenyl) thiazol-5-yl)methyl)-11-oxo-10, 11-dihydrodibenzo [b, f] [1, 4]oxazepine-8-carboxamide hydrochloride (1712)

To a stirring solution of compound 795 (150 mg, 0.26 mmol) in CH₂Cl₂ (3mL) under inert atmosphere was added 4 N HCl in 1, 4-dioxane (1.5 mL) at0° C.; warmed to RT and stirred for 2 h. The reaction was monitored byTLC; after completion of the reaction, the volatiles were removed invacuo to obtain the crude. The crude was washed with CH₂Cl₂ (2×5 mL) anddried in vacuo to afford 1712 (95 mg, 72%) as white solid. TLC: 10%MeOH/CH₂Cl₂ (R_(f): 0.2); ¹H-NMR (DMSO-d₆, 400 MHz): δ 10.67 (s, 1H),9.30 (t, J=5.8 Hz, 1H), 8.40 (br s, 3H), 7.93 (d, J=8.4 Hz, 2H), 7.81(s, 1H), 7.78 (dd, J=7.7, 1.7 Hz, 1H), 7.71 (s, 1H), 7.67-7.60 (m, 2H),7.57 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.3 Hz, 1H), 7.38-7.30 (m, 2H), 4.66(d, J=5.6 Hz, 2H), 4.06 (q, J=5.7 Hz, 2H); LC-MS: 99.11%; 457.0 (M⁺+1).(column; Ascentis Express C18, (50×3.0 mm, 2.7 μm); RT 1.79 min. 0.025%Aq. TFA+5% ACN: ACN+5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity):98.28%; (column; Zorbax SB C-18 (150×4.6 mm, 3.5 μm); RT 5.61 min.ACN+5% 0.05% TFA (Aq): 0.05% TFA (Aq)+5% ACN; 1.0 mL/min, Diluent:ACN:water).

Example 2: Assay Measuring Activity of Compounds on Viral Production inand on Viability of AD38 Cells

AD38 cells grown in a 175 cm flask with “Growth Medium” (DMEM/F12 (1:1)(cat #SH30023.01, Hyclone, 1× Pen/step (cat #: 30-002-CL, Mediatech,Inc), 10% FBS (cat #: 101, Tissue Culture Biologics), 250 μg/mL G418(cat #: 30-234-CR, Mediatech, Inc), 1 μg/mL Tetracycline (cat #: T3325,Teknova)) were detached with 0.25% trypsin. Tetracycline-free “treatmentmedium” (15 mL DMEM/F12 (1:1) (cat #SH30023.01, Hyclone, lx Pen/step(cat #: 30-002-CL, Mediatech, Inc), with 2% FBS, Tet-system approved(cat #: 631106, Clontech) were then added to mix and spun at 1300 rpmfor 5 min. Pelleted cells were then re-suspended/washed with 50 mL of1×PBS 2 times and 10 mL Treatment Medium one time. AD38 cells were thenre-suspended with 10 mL of Treatment Medium and counted. Wells of acollagen coated 96-well NUNC microtiter plate were seeded at 50,000/wellin 180 μL of Treatment Medium, and 20 μL of in treatment media witheither 10% DMSO (Control) or a 10× solution of compound in 10% DMSO wasadded. Plates were incubated for 6 days at 37° C.

Viral load production was assayed by quantitative PCR of the coresequence. Briefly, 5 μL of clarified supernatant was added to a PCRreaction mixture that contained forward primers HBV-f5′-CTGTGCCTTGGGTGGCTTT-3′, Reverse primers HBV-r5′-AAGGAAAGAAGTCAGAAGGCAAAA-3′ and Fluorescent TaqMan™ Probes HBV-probe5′-FAM/AGCTCCAAA/ZEN/TTCTTTATAAGGGTCGATGTCCATG/3IABkFQ-3′ in QuantaBiosciences PerfeCTa® qPCR Toughmix®, and was subsequently on an AppliedBiosystems VIIA7 in a final volume of 20 μL. The PCR mixture wasincubated at 45° C. for 5 minutes, then 95° C. for 10 min, followed by40 cycles of 10 seconds at 95° C. and 20 seconds at 60° C. Viral loadwas quantitated against known standards by using ViiA™ 7 Software. Viralload in the supernatant from wells with treated cells were comparedagainst viral load in supernatant from DMSO control wells (≥3 perplate).

At the end of compound treatment period cell viability was assessedusing a Promega CellTiter-Glo protocol. All supernatant was removed thepreviously treated 96-well microtiter plate, and 50 μL Tetracycline-freetreatment medium (DMEM/F12 (1:1), lx Pen/step (cat #: 30-002-CL,Mediatech, Inc), with 2% FBS, Tet-system approved (cat #: 631106,Clontech), and 1% DMSO was added back to each well. Another 50 μL ofCellTiter-Glo reagent solution (Promega, G7573) was then added at roomtemperature and the contents mixed for 2 minutes on an orbital shaker toinduce cell lysis. This was followed by incubation at room temperaturefor 10 minutes to stabilize the luminescent signal. The luminescence wasrecorded for 0.2 seconds per well on a Tecan multimode platereader(Infinite M1000 pro). The luminescent signal from each well wasnormalized against that of untreated (DMSO) control wells. All resultswere reported percent viability (with controls being 100%).

TABLE 5 Compounds and Biological activity AD38 Viral Load (%) (VL withAD38 Viability Normalized cmpd/VL in DMSO control) Result (cmpd/DMSO %)Example at 10 μM at 10 μM  1425 0.6 100  1432 21.8 101  1473 26.5 79 1496 9.6 57  1424 0.5 97  1431 5.5 103  1421 1.3 104  1525 0.2 104 1528 0.8 76  1526 0.8 94  1535 0.8 84  1546 2.2 97  1541 3.7 98  15442.6 88  1551 0.4 99  1557 0.6 98  1558 0.5 106  1548 0.4 97  1552 0.4102  1559 0.7 87  1529 2.0 97  1553 0.5 107  1562 0.9 97  1549 106.2 105 1556 1.6 105  1594 0.9 105  1592 1.3 99  1561 10.3 96  1566 0.6 95 1555 1.0 89  1595 0.3 109  1550 4.0 96  1584 1.4 101  1585 64.1 96 1589 80.0 98  1581 34.4 93  1587 2.8 99  1590 6.2 95  1596 3.8 25  15981.4 97  1606 3.0 91  1611 1.4 100  1618 1.9 100  1586 27.9 83  1599-A50.9 98  1604 0.9 82  1605 0.7 96  1607 52.8 98  1612-A 12.4 101  16172.2 101  1619 1.3 95  1620 41.9 103  1583 1.0 0  1599 5.9 61  1603 32.8108  1608 12.4 98  1612 6.9 105  1616 105.0 103  1621 25.9 81  1624 0.898  1602 59.8 97  1614 8.5 98  1615 54.9 103  1626 2.7 99  1629 3.2 107 1580 104.3 102  1625 51.9 96  1648 9.9 95  1661 45.2 90  1627 6.0 63 1628 21.8 95  1636 76.9 95  1650 58.8 82  1679 1.1 94  1698 2.7 91 1613-A 11.5 95  1637 2.3 101  1686 58.4 102  1687 49.2 102  1691 77.189  1645 6.7 101  1645-B 77.8 100  1654 0.5 94  1660 86.8 102  1668 23.4106  1694 61.1 91  1704 47.6 96  1732 18.8 100  1734 10.6 96  1645-A 0.398  1654-A 2.6 68  1680 15.0 94  1696 0.8 109  1664 0.6 99  1665 2.7 90 1673 3.2 105  1697 5.5 90  1703 3.1 93  1705 3.7 93  1712-1 5.2 97 1749 54.3 109  1752 29.8 98  1764 1.1 107  1770-A 29.8 100  1666 0.9 98 1670 0.9 102  1746 5.6 92  1747 3.0 95  1750 1.1 107  1753 2.4 97  17583.8 15  1760 6.4 94  1761 10.7 97  1766 1.3 98  1770 32.5 77  1675 2.3115  1677-A 2.3 103  1695 22.9 102  1701 2.1 94  1702 5.3 102  1735 3.192  1736-A 14.1 97  1738-A 1.8 104  1751 2.8 18  1754 1.6 93  1755 0.493  1667 0.5 93  1710 39.9 96  1711 6.5 96  1714-A 49.2 106  1736 6.8 94 1737 7.2 112  1738 2.9 93  1763 12.9 93  1769 43.3 101  1772 7.1 109 1653 65.4 108  1671-A 0.7 111  1767 0.5 94  1669 13.1 104  1671 18.2100  1677-B 2.4 89  1700 9.2 105  1706 57.5 103  1708 0.8 90  1709-A29.5 106  1672 0.6 101  1674 0.3 121  1709 51.1 94  1768 0.4 94  1806-A0.3 66  1707 10.7 88  1804-A 6.6 90  1805 0.6 97  1806 0.8 105  1804 0.5103  1815 0.2 88  1814 0.9 92  1817 0.3 97  1826 11.8 91  1838 1.4 113 1819 0.5 118  1820 3.2 105  1831 3.8 112  1832 14.1 98  1911 0.4 111 1855 2.5 102  1905 0.3 109  1910 19.0 94  1913 68.1 111  1915 15.7 100 1842 46.5 109  1857 1.5 107  1861 5.9 94  1862 19.9 107  1863 9.4 106 1917 1.1 108  1839 6.6 96  1840 3.2 107  1856 1.3 96  1860 7.5 98  18662.9 98  1877 0.2 96  1878 1.0 103  1914 120.4 77  1821 0.5 102  183367.4 102  1858 0.7 103  1859 2.7 89  1864 3.0 93  1904 0.5 89  1816 0.282  1835-A 0.3 89  1865 1.0 94  1921 1.2 101  1935 0.7 112  1893 2.0 91 1907 0.5 85  1879-A 2.5 121  1942 3.0 106  1823-A 5.8 92  1835 12.3 94 1841 9.1 104  1879 7.2 104  1908 7.0 94  1916 15.5 103  1932 2.2 101 1974 15.3 103  1823 5.2 96  1920 48.8 85  1922 60.3 39  1930 23.8 91 1934 40.0 69  1936 13.5 94  1941 5.2 84  1975 1.0 63  1885-A 4.5 107 1909 1.3 95  1929 1.2 93  1931 8.5 97  1822 1.5 89  1951 1.8 101  19581.5 91  1971 7.0 87  1943 1.9 98  1944 2.5 93  1947 2.3 101  1949 2.9 99 1954 0.5 106  1957 1.5 94  1960 0.8 106  1880 6.7 104  1880-A 0.7 124 1886 1.5 106  1927 4.7 92  1959 5.0 92  1970 1.5 121  1993 0.5 96  19067.8 89  1992 5.0 89 11002-A 1.0 106 11016-A 6.7 103 11017-A 8.8 102 1952 0.8 106  1953 0.4 118  1956 2.3 88 11016 38.8 106 11017 21.0 8611019 14.3 93 11019-A 1.0 95  1901-A 3.0 118  1901-B 69.4 108  1973 33.7100 11004 5.5 94 11018 3.9 98 11018-A 0.6 104 11041 47.4 94 11042 0.8109  1972 23.5 100  1981 0.2 105 11001 1.7 77 11002 0.9 90 11003 0.3 9711007-A 0.9 75 11043 12.0 100 11044 5.1 124  1881 0.8 108 11006 1.3 9711007 2.0 101 C38-02 0.5 94 11074 0.6 103  1995 16.3 103 11005 1.9 10211032-A 12.9 110 11038 2.0 99 11067 2.5 99 11073 2.2 94 11078 45.7 96 1889 4.6 98  1995-A 2.4 107 11039 1.9 92 11040 1.9 104 11053 3.6 10411079 3.3 102 11082 1.2 95 11083 0.8 62  1882 1.0 103  1990 4.1 98 1105414.1 102 11055 4.0 94 11056 0.8 96  1988 1.3 103  1991 2.0 98 11048 1.2103 11051 1.2 103 11057 1.0 101 11077 0.9 90  1989 2.5 90  1994 0.9 9211046 0.9 100 11047 1.4 96 11050 0.7 96 11080 1.4 84 11084 9.7 91 110864.7 88  1998 3.7 99 11011 5.3 98 11045 0.6 94 11085 3.4 88 11087 7.1 10311088 17.9 100 11093 4.6 102 11094 0.6 94 11102 0.5 93 11104-A 0.9 74C20-01 1.5 98 C20-02 0.5 95 C38-01 1.3 99  1888 1.2 100 11028 5.2 9211029 5.3 105 11063 1.2 102 11063-A 0.4 104 11091 1.3 89 11103 2.5 10211104 9.4 97 11116 0.9 97 11131 2.0 88  1997 9.7 104 11026 5.5 100 110490.8 89 11063-B 5.4 95 11065 1.2 66 11066 0.4 104 11092 0.5 101 11099 3.990 11101 1.9 85 11118 1.9 95 11134 1.4 90 11135 1.8 91 11106 3.3 9711106-A 3.6 90 11137 3.6 96 11148 0.3 98 11149 0.2 100 11032 51.7 10311033 17.1 95 11064 4.1 85 11100 6.8 102 11150 0.4 100 11152 1.6 96C51-01 0.4 99 C51-02 0.2 98 11105 1.6 95 11107-A 7.7 100 11112 4.0 10011117-A 0.3 110 11142 0.8 87 11158 6.4 100 11160 17.7 104 11162 8.7 10411182 0.7 104  1996 17.4 100 11061 0.9 95 11107 6.4 96 11108 11.2 9511108-B 0.8 101 11113 4.9 92 11138 1.0 96 11139 5.5 104 11140 5.5 9911161 1.7 104 C44-01 2.6 97

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those itemslisted below, are hereby incorporated by reference in their entirety forall purposes as if each individual publication or patent wasspecifically and individually incorporated by reference. In case ofconflict, the present application, including any definitions herein,will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification. The full scope of the inventionshould be determined by reference to the claims, along with their fullscope of equivalents, and the specification, along with such variations.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in this specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained by the present invention.

What is claimed is:
 1. A compound represented by:

wherein Y is O; R^(Z) is selected from the group consisting of H,methyl, ethyl, propyl, phenyl and benzyl; R^(m′) and R^(m) are eachindependently selected from the group consisting of H, C₁₋₆alkyl(optionally substituted by one, two or three substituents eachindependently selected from halogen and hydroxyl), and C₂₋₆alkenyl(optionally substituted by one, two or three substituents eachindependently selected from halogen and hydroxyl); R^(c) is selectedfrom the group consisting of H, C₁₋₆alkyl and C₂₋₆alkenyl; R⁷⁷ isselected from the group consisting of H, halogen, cyano, and C₁₋₆alkyl;R⁷⁸ is phenyl (optionally substituted with one, two, three or foursubstituents each independently selected from the group consisting ofR⁷³); X² is selected from the group consisting of S(O)_(w) (wherein w is0, 1, or 2), O, —C(O)— and NR′, R⁷⁹ is selected from the groupconsisting of H, hydroxyl, halogen, C₁₋₆alkyl, —C(O)—O—C₁₋₆alkyl,heterocycle (optionally substituted by one or more substituents selectedfrom the group consisting of halogen, NR′R′, —C(O)—O—C₁₋₆alkyl, carboxyand C₁₋₆alkyl), —C(O)—NR′R″, —C(═NH)—NR′R″, heteroaryl, phenyl(optionally substituted by one or more substituents selected from thegroup consisting of halogen, NR′R′, —C(O)—O—C₁₋₆alkyl, carboxy,C₁₋₆alkoxy, and C₁₋₆alkyl), C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,carboxy, NR′R″, —C(O)—C₁₋₆alkyl, C₃₋₆cycloalkyl, —NR′—C(O)— C₁₋₆alkyl,NR′—C(O)— O—C₁₋₆alkyl, —S(O)_(w)—C₁₋₆alkyl (where w is 0, 1 or 2),—S(O)_(w)—NR′R″ (where w is 0, 1 or 2), and —NR′—S(O)_(w)— C₁₋₆alkyl(where w is 0, 1 or 2)); R⁷³ is selected from the group consisting of H,halogen, hydroxyl, nitro, cyano, carboxy, oxo, C₁₋₆alkyl,—C(O)—O—C₁₋₆alkyl, heterocycle (optionally substituted by one or moresubstituents selected from the group consisting of halogen, hydroxyl,oxo, NR′R′, —C(O)—O—C₁₋₆alkyl, carboxy and C₁₋₆alkyl),—C(O)—NR′—C₁₋₆alkyl, —C(═NH)—NR′R″, heteroaryl, phenyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, carboxy, oxo, NR′R″, —C(O)—C₁₋₆alkyl,—C₃₋₆cycloalkyl, NR′—C(O)— C₁₋₆alkyl, NR′—C(O)— O—C₁₋₆alkyl,—S(O)_(w)—C₁₋₆alkyl (where w is 0, 1 or 2), —S(O)_(w)—NR′R″ (where w is1, 2 or 3), —NR′—S(O)_(w)— C₁₋₆alkyl (where w is 0, 1 or 2), C(O)—NR′—C₁₋₆alkyl, C(O)—C₁₋₃alkylene-NR′— C(O)—O— C₁₋₆alkyl, X²— R⁷⁹; andX²—C₁₋₆alkylene-R⁷⁹; R′ is selected, independently for each occurrence,from H, methyl, ethyl, cyclopropyl, cyclobutyl, and propyl; R″ isselected, independently for each occurrence, from H, methyl, ethyl,propyl, (optionally substituted by hydroxyl), butyl (optionallysubstituted by hydroxyl), —C(O)-methyl and —C(O)-ethyl, or R′ and R″taken together with the nitrogen to which they are attached may form a4-7 membered heterocycle optionally substituted by one, two or moresubstituents selected from the group consisting of halogen, hydroxyl,NH₂, —C(O)—O—C₁₋₃alkyl, —C(O)—C₁₋₃alkyl, carboxy, oxo, and C₁₋₃alkyl;each of moieties R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independentlyselected for each occurrence from the group consisting of hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy, C₂₋₆alkynyl, C₂₋₆alkenyl, halogen, hydroxyl,nitro, cyano, and NR′R″; wherein for each occurrence, C₁₋₆alkyl,C₂₋₆alkenyl or C₂₋₆alkynyl may be optionally substituted with one, two,three or more substituents selected from the group consisting ofhalogen, hydroxyl, nitro, cyano, carboxy, C₃₋₆cycloalkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, C₁₋₃alkoxy, NR′R″, —NR′—S(O)_(w)— C₁₋₂alkyl (where w is 0,1 or 2), NR′—C(O)—C₁₋₃alkyl, NR′—C(O)— O—C₁₋₃alkyl, andS(O)_(w)—NR′R″(where w is 0, 1 or 2); C₁₋₆alkoxy may be optionallysubstituted with one, two, three or more substituents selected from thegroup consisting of halogen, hydroxyl, nitro, cyano, carboxy, C₁₋₃alkyl,NR′R″, —NR′—S(O)_(w)— C₁₋₂alkyl (where w is 0, 1 or 2), andS(O)_(w)—NR′R″ (where w is 0, 1 or 2); C₁₋₆alkylene may be optionallysubstituted by a substituent selected from the group consisting ofC₃₋₆cycloalkyl, hydroxyl, cyano, and halogen; and pharmaceuticallyacceptable salts and N-oxides thereof.
 2. The compound of claim 1,wherein R⁷⁷ is selected from the group consisting of H, CH₃ and CF₃. 3.The compound of claim 1, wherein R⁷ is H or halogen.
 4. The compound ofclaim 1, wherein R¹⁰ is H, halogen or methyl.
 5. The compound of claim1, wherein R^(m′) and R^(m) are each H.
 6. The compound of claim 1,wherein R^(Z) is H.
 7. The compound of claim 1, wherein each of R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, and R¹⁰ is H.
 8. The compound of claim 1, wherein R⁷⁷ isH.
 9. A pharmaceutically acceptable composition comprising a compound ofclaim 1, and a pharmaceutically acceptable excipient.
 10. A method oftreating a hepatitis B infection in a patient in need thereof,comprising administering an effective amount of a compound of claim 1.11. A method of treating a hepatitis B infection in a patient in needthereof, comprising administering a first compound selected from acompound of claim 1, and optionally administering one or more additionalcompounds.
 12. A method of treating a hepatitis B infection in a patientin need thereof, comprising administering an amount of a compound ofclaim 1, and administering another HBV capsid assembly promoter.